Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel.

BACKGROUND: Medication management for people living with dementia is a complex task as it is unclear what constitutes optimal medication management in this population due to the shifting focus of health priorities and the balance between the benefits and harms of medications. AIM: This study sought expert opinion to create a consensus list to define appropriate medication management of co-morbidities for people with dementia. METHODS: This study used the Delphi technique. We invited multidisciplinary experts in geriatric therapeutics including pharmacists, doctors, nurse practitioners, a patient advocate and a psychologist to participate. Participants were asked to engage into three or more rounds of questioning. Round 1 was a questionnaire comprised of one question defining dementia and seven open-ended questions about appropriate management of co-morbidities in people with dementia. Two investigators qualitatively analysed the responses to questions from Round 1 using thematic analysis. The results of this analysis were provided to participants as statements in the Round 2 survey. The participants were asked to rate their agreement with each statement on a 5-point Likert scale. The median and interquartile range (IQR) were calculated for the responses to each statement. Consensus was pre-specified as an IQR less than or equal to 1. Statements where consensus was not achieved were presented to participants in Round 3. The Round 2 median and IQR values were provided and participants were again asked to rate their agreement with each statement on a 5-point Likert scale. The statements where participants agreed or strongly agreed were included in the Medication Appropriateness Tool for Co-morbid Health conditions in Dementia criteria. RESULTS: Fifty-seven experts agreed to participate in the study, of whom 58% were pharmacists and 36% were medical practitioners. Fifty-five participants completed the Round 1 (95% response rate). A total of 128 statements was included in the Round 2 survey. Consensus was reached on 93 statements in Round 2 (n = 48 responders, 84% response rate) and on 18 statements in Round 3 (n = 43 responders, 75% response rate). The participants reached consensus on 111 of 128 statements. Of these statements, 67 statements were included in the Medication Appropriateness Tool for Co-morbid Health conditions in Dementia criteria. The statements were in the broad themes of preventative medication, symptom management, disease progression, psychoactive medication, treatment goals, principles of medication use, side-effects and medication reviews. DISCUSSION: This research provides consensus-based guidance for clinicians who manage co-morbid health conditions in people with dementia.

Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase.

Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function.

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts.

Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.

Metabolic stress, IAPP and islet amyloid.

Amyloid forms within pancreatic islets in type 2 diabetes from aggregates of the ß-cell peptide islet amyloid polypeptide (IAPP). These aggregates are toxic to ß-cells, inducing ß-cell death and dysfunction, as well as inciting islet inflammation. The ß-cell is subject to a number of other stressors, including insulin resistance and hyperglycaemia, that may contribute to amyloid formation by increasing IAPP production by the ß-cell. ß-Cell dysfunction, evident as impaired glucose-stimulated insulin secretion and defective prohormone processing and exacerbated by metabolic stress, is also a likely prerequisite for islet amyloid formation to occur in type 2 diabetes. Islet transplants in patients with type 1 diabetes face similar stressors, and are subject to rapid amyloid formation and impaired proinsulin processing associated with progressive loss of ß-cell function and mass. Declining ß-cell mass is predicted to increase metabolic demand on remaining ß-cells, promoting a feed-forward cycle of ß-cell decline.

Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

Human islet amyloid polypeptide (hIAPP) is a cytotoxic protein that aggregates into oligomers and fibrils that kill pancreatic ß-cells. Here we analyze hIAPP aggregation in vitro, measured via thioflavin-T fluorescence. We use mass-action kinetics and scaling analysis to reconstruct the aggregation pathway, and find that the initiation step requires four hIAPP monomers. After this step, monomers join the nucleus in pairs, until the first stable nucleus (of size approximately 20 monomers) is formed. This nucleus then elongates by successive addition of single monomers. We find that the best-fit of our data is achieved when we include a secondary fibril-dependent nucleation pathway in the reaction scheme. We predict how interventions that change rates of fibril elongation or nucleation rates affect the accumulation of potentially cytotoxic oligomer species. Our results demonstrate the power of scaling analysis in reverse engineering biochemical aggregation pathways.

Aquatic contaminants in Solomon Islands and Vanuatu: Evidence from passive samplers and Microtox toxicity assessment.

Water Quality issues in many Pacific countries are rising, with the increase in coastal populations and associated urban runoff but management requires contamination issues in the aquatic environment to be identified and prioritised. In Vanuatu and Solomon Islands there are few laboratories and resources to assess for the presence or impact of complex chemical contaminants. The extent and impact of chemical contamination of the marine and coastal environment is poorly described. Passive chemical samplers were used to measure a range of aquatic pollutants around the capital cities, Honiara (Solomon Islands) and Port Vila (Vanuatu). We detected a range of chemicals indicative of agricultural and industrial contamination and a few sites had concerning concentrations of specific hydrocarbons and pesticides. The rapid ecotoxicology test, Microtox, indicated toxic impacts in rivers, coastal sites and urban drains This work provides new data on chemical contamination and possible impacts of that contamination for both countries. The techniques could be applied widely across the region to generate critical data for environmental management, guide monitoring efforts and measure the impact of policy or land-use changes.

Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?

Type 2 diabetes is a progressive disease characterised by islet amyloid deposits in the majority of patients. Amyloid formation is considered a significant factor in deterioration of islet function and reduction in beta cell mass, and involves aggregation of monomers of the normally soluble beta cell peptide, human islet amyloid polypeptide (hIAPP) into oligomers, fibrils and, ultimately, mature amyloid deposits. Despite extensive in vitro studies, the process of hIAPP aggregation in vivo is poorly understood, though it is widely reported to promote cytotoxicity. Recently, studies have suggested that only the early stages of fibril assembly, and in particular small hIAPP oligomers, are responsible for beta cell cytotoxicity. This challenges the prior concept that newly formed fibrils and/or mature fibrillar amyloid are cytotoxic. Herein, evidence both for and against the toxic hIAPP oligomer hypothesis is presented; from this, it is apparent that what exactly causes beta cell death when hIAPP aggregates remains debatable. Moreover, substantially more work with more specific reagents and techniques than are currently available will be required to identify conclusively the toxic species resulting from hIAPP aggregation. Keeping an open mind on the nature of the cytotoxic insult has implications for therapeutic developments and clinical care in type 2 diabetes.

Molecular characterization of a cross-reactive idiotope on human immunoglobulins utilizing the VH4-21 gene segment.

The anti-idiotypic (anti-Id) antibody (Ab) 9G4 binds a cross-reactive idiotope (CRI) present in a select group of human autoantibodies. This Id has been localized to the portion of immunoglobulin (Ig) heavy (H) chains encoded by the VH4-21 gene segment, a member of the human VH4 family. This gene segment is utilized by essentially all cold agglutinin (CA) Abs with I/i specificity isolated from patients with CA disease stemming from chronic lymphoproliferative disorders. In this study, mutational analysis of a CA has been used to determine the structural basis for 9G4 binding to Abs utilizing the VH4-21 gene segment. Recombinant CA H chain mutants were produced and their 9G4 reactivity determined. Mutants were generated by exchanging VH4-21 sequences in the FR1, CDR1, and CDR2 with corresponding sequences from a closely related gene segment V71-2, a VH4 family member that is associated neither with Abs having CA activity nor with Abs that react with 9G4. The results indicate that the motif AVY at amino acid positions 23-25 in FR1 defines the 9G4 idiotope. Reaction of these recombinant Abs with a polyclonal rabbit anti-CA antiserum absorbed to render it specific for a CA CRI also maps predominantly to FR1. These findings indicate that the solvent-exposed FR1 plays an important role in eliciting an immune response to Igs.

Somatic hypermutation introduces insertions and deletions into immunoglobulin V genes.

During a germinal center reaction, random mutations are introduced into immunoglobulin V genes to increase the affinity of antibody molecules and to further diversify the B cell repertoire. Antigen-directed selection of B cell clones that generate high affinity surface Ig results in the affinity maturation of the antibody response. The mutations of Ig genes are typically basepair substitutions, although DNA insertions and deletions have been reported to occur at a low frequency. In this study, we describe five insertion and four deletion events in otherwise somatically mutated VH gene cDNA molecules. Two of these insertions and all four deletions were obtained through the sequencing of 395 cDNA clones (approximately 110,000 nucleotides) from CD38+IgD- germinal center, and CD38-IgD- memory B cell populations from a single human tonsil. No germline genes that could have encoded these six cDNA clones were found after an extensive characterization of the genomic VH4 repertoire of the tonsil donor. These six insertions or deletions and three additional insertion events isolated from other sources occurred as triplets or multiples thereof, leaving the transcripts in frame. Additionally, 8 of 9 of these events occurred in the CDR1 or CDR2, following a pattern consistent with selection, and making it unlikely that these events were artifacts of the experimental system. The lack of similar instances in unmutated IgD+CD38- follicular mantle cDNA clones statistically associates these events to the somatic hypermutation process (P = 0.014). Close scrutiny of the 9 insertion/deletion events reported here, and of 25 additional insertions or deletions collected from the literature, suggest that secondary structural elements in the DNA sequences capable of producing loop intermediates may be a prerequisite in most instances. Furthermore, these events most frequently involve sequence motifs resembling known intrinsic hotspots of somatic hypermutation. These insertion/deletion events are consistent with models of somatic hypermutation involving an unstable polymerase enzyme complex lacking proofreading capabilities, and suggest a downregulation or alteration of DNA repair at the V locus during the hypermutation process.

Optically defined multifunctional patterning of photosensitive thin-film silica mesophases.

Photosensitive films incorporating molecular photoacid generators compartmentalized within a silica-surfactant mesophase were prepared by an evaporation-induced self-assembly process. Ultraviolet exposure promoted localized acid-catalyzed siloxane condensation, which can be used for selective etching of unexposed regions; for "gray-scale" patterning of refractive index, pore size, surface area, and wetting behavior; and for optically defining a mesophase transformation (from hexagonal to tetragonal) within the film. The ability to optically define and continuously control both structure and function on the macro- and mesoscales is of interest for sensor arrays, nanoreactors, photonic and fluidic devices, and low-dielectric-constant films.

Simultaneous magnetically directed drug convection and MR imaging.

Superparamagnetic iron oxide nanoparticles (IO NPs) are of interest for their usefulness in biomedical applications. In this work, we have synthesized iron oxide nanocomposites surface-modified with different biocompatible polymers. Bovine serum albumin (BSA) was physisorbed onto these IO NPs along with an excipient during freeze-drying. The mass transport of the protein attached to the iron oxide core-shell nanoparticles (IO cs-NPs) under a gradient magnetic field of an MRI instrument was observed in vitro and in an egg as a model system for a biological fluid. From the in vitro experiments in agarose gels, it was observed that the protein gets separated from the core during mass transport for some cs-IO, but co-migration was observed for PEG-modified IO cs-NPs. These experiments demonstrated proof-of-concept for the use of IO cs-NPs in magnetically directed drug convection.

Intrinsic electronic transitions of the absorption spectrum of (OPy)2Ti(TAP)2: implications toward photostructural modifications.

Theoretical calculations based on time-dependent density functional theory are used to characterize the electronic absorption spectrum of a heteroleptic Ti-alkoxide molecule, (OPy)(2)Ti(TAP)(2) [OPy = pyridine carbinoxide, TAP = 2,4,6 tris(dimethylamino)phenoxide] under investigation as a photosensitive precursor for use in optically initiated solution synthesis of the metal oxide. Computational results support the assignment of UV absorption features observed in solid-state precursor films to key intrinsic ground-state transitions that involve ligand-to-metal charge transfer and pi-pi* transitions within the cyclic ligand moieties present. The nature of electron density redistribution associated with these transitions provides early insight into the excitation wavelength dependence of photostructural modification previously observed in this precursor system.

Quasi-Isotropic and Pseudo-Ductile Highly Aligned Discontinuous Fibre Composites Manufactured with the HiPerDiF (High Performance Discontinuous Fibre) Technology.

Conventional composite materials reinforced with continuous fibres display high specific strength but have a number of drawbacks including: the elastic-brittle behaviour, difficulties in producing defect-free components of complex shape with high-volume automated manufacturing processes, and inherent lack of recyclability. Highly aligned, discontinuous fibre-reinforced composites (ADFRCs) are truly beneficial for mass production applications, with the potential to offer better formability and comparable mechanical properties with continuous fibre-reinforced composites. In previous publications, the High Performance Discontinuous Fibre (HiPerDiF) technology has been shown to offer the possibility to intimately hybridise different types of fibres, to achieve pseudo-ductile tensile behaviour, and remanufacture reclaimed fibres into high-performance recycled composites. However, to date, the work has been conducted with unidirectional (UD) laminates, which is of limited interest in engineering applications with mechanical stresses acting across many directions; this paper reports, for the first time, the mechanical behaviour of quasi-isotropic (QI) ADFRCs. When compared with randomly-oriented discontinuous fibre composites (RODFRCs), QI ADFRCs offer enhanced stiffness (+26%) and strength (+77%) with higher consistency, i.e., a reduction of the coefficient of variance from the 25% of RODFRCs to the 6% of ADFRCs. Furthermore, hybrid QI ADFRCs retain the pseudo-ductility tensile behaviour previously observed in unidirectional (UD) lay-up.

Pharmacological inhibitors of NF-kappaB accelerate apoptosis in chronic lymphocytic leukaemia cells.

Nuclear factor-kappaB (NF-kappaB) is a transcription factor that plays a critical role in the inappropriate survival of various types of malignant cells. Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the Western world. Although overexpression and regulation of NF-kappaB has been described in CLL, its function remains unclear. Exposure of CLL cells to BAY117082 or Kamebakaurin, potent pharmacological inhibitors of the NF-kappaB pathway, accelerated apoptosis in approximately 70% of cases. Sensitivity to NF-kappaB pathway inhibitors was not related to the prognostic markers VH status, CD38 or Zap70 expression, or to the levels of nuclear NF-kappaB. Normal peripheral B cells were resistant to the apoptosis-inducing effects of these compounds. Cell death induced by the inhibitors was associated with activation of caspase-9 and -3, and loss of mitochondrial membrane polarization, but did not involve changes in the expression of Bcl-2 or Mcl-1. Inhibitors caused an increase in c-jun NH2-terminal kinase activity in CLL, but this did not appear to be important for apoptosis. Microarray analysis identified some potential novel NF-kappaB target genes, including interleukin-16- and the Bcl-2- related survival protein Bcl-w. These results demonstrate that a substantial proportion of CLL are dependent on NF-kappaB for enhanced survival and suggest that inhibition of NF-kappaB may have therapeutic potential.

Metastatic endometrial cancer of the paranasal sinuses.

Endometrial carcinoma is the fourth most common cancer affecting women in the UK. Its most frequent sites of spread are to the pelvic and para-aortic lymph nodes, vagina and peritoneum. We report a case of a 63-year-old woman with known endometrial cancer who presented with left facial swelling and eye displacement. Investigations revealed an expansile soft-tissue density mass arising within the bone, centred on the left zygoma, with exophytic extension into the left maxillary antrum, infratemporal fossa and inferiorly into the orbit. Endoscopic biopsies were taken and histology confirmed metastatic deposits of endometrial cancer. Clinicians should be aware that distant spread of endometrial cancer is linked with advanced disseminated disease and palliative treatments should be considered.

THE EFFECTS OF THE ALKALOID SCOPOLAMINE ON THE PERFORMANCE AND BEHAVIOR OF TWO CATERPILLAR SPECIES.

Plants have evolved many defenses against insect herbivores, including numerous chemicals that can reduce herbivore growth, performance, and fitness. One group of chemicals, the tropane alkaloids, is commonly found in the nightshade family (Solanaceae) and has been thought to reduce performance and fitness in insects. We examined the effects of the tropane alkaloid scopolamine, the alkaloid constituent of Datura wrightii, which is the most frequent host plant for the abundant and widespread insect herbivore Manduca sexta in the southwestern United States. We exposed caterpillars of two different species to scopolamine: M. sexta, which has a shared evolutionary history with Datura and other solanceous plants, and Galleria mellonella, which does not. We showed that the addition of ecologically-realistic levels of scopolamine to both the diet and the hemolymph of these two caterpillar species (M. sexta and G. mellonella) had no effect on the growth of either species. We also showed that M. sexta has no behavioral preference for or against scopolamine incorporated into an artificial diet. These results are contrary to other work showing marked differences in performance for other insect species when exposed to scopolamine, and provide evidence that scopolamine might not provide the broad-spectrum herbivore resistance typically attributed to it. It also helps to clarify the coevolutionary relationship between M. sexta and one of its main host plants, as well as the physiological mechanism of resistance against scopolamine.

The convergence of regenerative medicine and rehabilitation: federal perspectives.

Regenerative rehabilitation is the synergistic integration of principles and approaches from the regenerative medicine and rehabilitation fields, with the goal of optimizing form and function as well as patient independence. Regenerative medicine approaches for repairing or replacing damaged tissue or whole organs vary from utilizing cells (e.g., stem cells), to biologics (e.g., growth factors), to approaches using biomaterials and scaffolds, to any combination of these. While regenerative medicine offers tremendous clinical promise, regenerative rehabilitation offers the opportunity to positively influence regenerative medicine by inclusion of principles from rehabilitation sciences. Regenerative medicine by itself may not be sufficient to ensure successful translation into improving the function of those in the most need. Conversely, with a better understanding of regenerative medicine principals, rehabilitation researchers can better tailor rehabilitation efforts to accommodate and maximize the potential of regenerative approaches. Regenerative rehabilitative strategies can include activity-mediated plasticity, exercise dosing, electrical stimulation, and nutritional enhancers. Critical barriers in translating regenerative medicine techniques into humans may be difficult to overcome if preclinical studies do not consider outcomes that typically fall in the rehabilitation research domain, such as function, range of motion, sensation, and pain. The authors believe that encouraging clinicians and researchers from multiple disciplines to work collaboratively and synergistically will maximize restoration of function and quality of life for disabled and/or injured patients, including U.S. Veterans and Military Service Members (MSMs). Federal Government agencies have been investing in research and clinical care efforts focused on regenerative medicine (NIH, NSF, VA, and DoD), rehabilitation sciences (VA, NIH, NSF, DoD) and, more recently, regenerative rehabilitation (NIH and VA). As science advances and technology matures, researchers need to consider the integrative approach of regenerative rehabilitation to maximize the outcome to fully restore the function of patients.

Potential of selective insecticides for managing Uraba lugens (Lepidoptera: Nolidae) on Eucalypts.

The leaf skeletonizer Uraba lugens Walker (Lepidoptera: Nolidae), an Australian species, locally known as "gumleaf skeletonizer", is well established in New Zealand. This insect has the potential to become a serious pest of forestry and amenity eucalypts (Eucalyptus spp.) and is the focus of a long-term management program. The use of synthetic chemical or biological insecticides is one possible control method within an integrated control program. A series of dose-response trials were conducted using laboratory bioassays to test the efficacy of several insecticides against U. lugens: pyrethroids, spinosad, Bacillus thuringiensis kurstaki Berliner (Btk) and an insect growth regulator, Mimic. Pyrethroids and spinosad proved highly effective against U. lugens larvae, achieving 100% mortality after 3-6-d exposure. The performance of Btk was lower against gregarious skeletonizing larvae compared with solitary chewing larvae. When good coverage of the target foliage is achieved, >90% mortality is possible with Btk. Mimic performed poorly against U. lugens compared with other insecticides tested (<60% mortality). The Eucalyptus species on which larvae were feeding significantly altered insecticide efficacy. Treatments applied to Eucalyptus nitens (Deane & Maiden) Maiden had reduced efficacy compared with E. cinerea F. Muell. ex Benth. or E. fastigata Deane & Maiden. Cooler temperatures also reduced insecticide efficacy, presumably by decreasing movement and food consumption by U. lugens. Recommendations on spray applications to control U. lugens in New Zealand are given.

Magnetic resonance microscopy studies of cation diffusion in cartilage.

The diffusion of copper ions in bovine nasal cartilage (BNC), a dense connective tissue, was investigated to further the understanding of ion transport in charged biopolymer systems. Using an inversion-recovery null-point imaging technique, it was found that the diffusion rate of divalent copper ions into cartilage was significantly lower in normal BNC than in BNC in which the matrix fixed charges had been reduced by enzymatic digestion or acid neutralization. In normal cartilage, counterion diffusion was not well described by a simple Fickian process, likely owing to the high charge density of the constituent molecules. In contrast, in both digested and acid neutralized BNC, counterion diffusion appeared Fickian. Features of the ion transport process were modeled using a diffusion equation which included a linear sorption term to account for cation binding. The diffusion coefficient of copper in cartilage increased with decreasing matrix fixed charge and was constant for reservoir concentrations up to 30 mM. The activation energy for the diffusion of copper into BNC was determined to be 34.5 kJ/mol.

Immunogenetic analysis reveals that epitope shifting occurs during B-cell affinity maturation in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a liver disease characterized by serum autoantibodies against the pyruvate dehydrogenase complex (PDC) located in the inner mitochondrial membrane. The predominant target in PDC has previously been localized to the inner lipoyl domain (ILD) of the E2 subunit. The etiology of PBC is unknown, although molecular mimicry with bacterial PDC has been proposed. Here, we have investigated the etiology of PBC and nature of the autoimmune response by analyzing the structure of a human monoclonal antibody with ILD specificity. Mutants of the monoclonal antibody, which was originally isolated from a patient with PBC, were expressed as Fab by phage display, and tested for reactivity against recombinant domains of the E2 subunit. Fab in which the V(H)-encoded portions were reverted to germline lost reactivity against the ILD alone, but recognized a different epitope in a didomain construct encompassing the ILD, hinge region and E1/E3 binding domain. The complete V(H) and V(L )germline revertant was unreactive with the human ILD and didomain, the Escherichia coli didomain, and whole PDC. We hypothesize that the IgM on the surface of the naïve B-cell first recognizes an as yet unidentified antigen, and that accumulation of somatic mutations results in an intermolecular epitope shift directed towards an epitope involving the E1/E3 binding domain. Further mutations result in the specificity being redirected to the ILD. These findings also suggest that bacterial molecular mimicry is not involved in initiating disease.