The Interleukin-1 Receptor-Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial.

Objective: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting.

Methods: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs.

41-Week Study of Progressive Diabetic Nephropathy in the ZSF1 fa/fa Rat Model.

This symposium synopsis summarizes key results from a 41-week study of diabetic nephropathy (DN) in the type 2 diabetic ZSF1 fa/fa rat model. During this study, we conducted longitudinal analysis of biomarkers, renal histopathology, ultrastructural assessment, renal quantitative image analysis, and transcriptome analysis of glomerular-enriched tissue. We concluded that there is translational value for using the ZSF1 rat model in mechanistic and therapeutic intervention efficacy studies for type 2 DN.

High resolution molecular and histological analysis of renal disease progression in ZSF1 fa/faCP rats, a model of type 2 diabetic nephropathy.

ZSF1 rats exhibit spontaneous nephropathy secondary to obesity, hypertension, and diabetes, and have gained interest as a model system with potentially high translational value to progressive human disease. To thoroughly characterize this model, and to better understand how closely it recapitulates human disease, we performed a high resolution longitudinal analysis of renal disease progression in ZSF1 rats spanning from early disease to end stage renal disease. Analyses included metabolic endpoints, renal histology and ultrastructure, evaluation of a urinary biomarker of fibrosis, and transcriptome analysis of glomerular-enriched tissue over the course of disease.

Identification of Promising Urinary MicroRNA Biomarkers in Two Rat Models of Glomerular Injury.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate protein levels posttranscriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers.

Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.

Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration.

Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms.

Background: MicroRNAs (miRNAs) are small, non-coding RNAs that regulate protein levels post-transcriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers.

Selective inhibition of BTK prevents murine lupus and antibody-mediated glomerulonephritis.

Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling.

Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy.

We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety.

Neurological disease in wild loggerhead sea turtles Caretta caretta.

Beginning in October 2000, subadult loggerhead sea turtles Caretta caretta showing clinical signs of a neurological disorder were found in waters off south Florida, USA. Histopathology indicated generalized and neurologic spirorchiidiasis. In loggerhead sea turtles (LST) with neurospirorchiidiasis, adult trematodes were found in the meninges of the brain and spinal cord of 7 and 3 affected turtles respectively, and multiple encephalic intravascular or perivascular eggs were associated with granulomatous or mixed leukocytic inflammation, vasculitis, edema, axonal degeneration and occasional necrosis.

Potential sites of virus latency associated with indigenous pseudorabies viruses in feral swine.

Free-ranging feral swine (Sus scrofa) are known to be present in at least 32 states of the USA and are continuously expanding their range. Infection with pseudorabies virus (PRV) occurs in feral swine and the primary route of transmission in free-living conditions seems to be venereal. Between 1995 and 1999, naturally infected feral swine and experimentally infected hybrid progeny of feral and domestic swine, were kept in isolation and evaluated for occurrence of latent PRV indigenous to feral swine in sacral and trigeminal ganglia and tonsil.

An outbreak of fungal dermatitis and stomatitis in a free-ranging population of pigmy rattlesnakes (Sistrurus miliarius barbouri) in Florida.

Between September 1997 and March 1998, a severe skin, eye, and mouth disease was observed in a population of dusky pigmy rattlesnakes (Sistrurus miliarius barbouri), at the Lake Woodruff National Wildlife Refuge in Volusia County, Florida (USA). Three affected pigmy rattlesnakes were submitted for necropsy. All snakes had severe necrotizing and predominantly granulomatous dermatitis, stomatitis, and ophthalmitis, with involvement of the subadjacent musculature and other soft tissues.

Pathogenicity of Haemoproteus danilewskyi, Kruse, 1890, in blue jays (Cyanocitta cristata).

Although the impact of blood parasite infections on passerine birds is potentially great, little is known of their pathologic effects. We studied Haemoproteus danilewskyi in experimentally infected captive and naturally infected free-ranging blue jays (Cyanocitta cristata) to determine patterns of infection and examine the pathologic effects of the parasite on the host. Physiologic changes, such as elevated numbers of lymphocytes, heterophils, basophils, eosinophils, and monocytes and decreased packed cell volume in the peripheral blood were associated with the erythrocytic phase of experimental infections of captive juvenile jays.

Retrospective study of proliferative papillary vulvitis in Florida panthers.

Proliferative, papillary vulvitis was identified in 16 of 34 (47%) free-ranging and captive female Florida panthers (Puma concolor coryi) monitored over a period from 1983-98. Gross lesions were characterized by extensive papilliferous proliferation in the mucosa of the vestibulum vaginae. Within lesions, the mean length and width of vestibular papillae were 1.

Causes of mortality of free-ranging Florida panthers.

The Florida panther (Puma concolor coryi) is one of the most endangered mammals, with the entire population estimated to consist of only 30-50 adult animals. Between 1978 and 1999, 73 free-ranging Florida panther carcasses were submitted for postmortem evaluation, of which 47 (64%) were radiocollared and 26 (36%) were uncollared cats. Overall, mortality of panthers > 6-mo-old was due to vehicular trauma in 25 (35%), intraspecific aggression in 19 (26%), illegal kill in seven (10%), research activities in two (3%), infectious diseases in two (3%), esophageal tear in one (1%), pleuritis in one (1%), pyothorax in one (1%), aortic aneurysm in one (1%), atrial septal defect in one (1%), and causes of death were undetermined in 13 (18%) due to autolysis.

Aplastic anemia associated with prolonged high-dose trimethoprim-sulfadiazine administration in two dogs.

Trimethoprim-sulfadiazine (TMP-SDZ) (Tribressin tablets 120 - 100 mg sulfadiazine, 20-mg trimethoprim [Coopers Animal Health, Inc., A Pitman-Moore Company, Mundelein, Ill.]) is a broad spectrum antibiotic combination effective in the treatment of bacterial pneumonia, urinary tract infections, pyoderma, meningitis, and prostatitis.