Clinical features and amino acid profiles of dogs with hepatocutaneous syndrome or hepatocutaneous-associated hepatopathy.

BACKGROUND: Superficial necrolytic dermatitis (SND), hepatocutaneous-associated hepatopathy (HCH), aminoaciduria, and hypoaminoacidemia define hepatocutaneous syndrome (HCS) in dogs. Dogs without SND but that possess all other syndrome components are not well described. HYPOTHESIS/OBJECTIVES: To define an inclusive syndrome, aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES) for dogs with HCH or HCS. Compare clinical features, salient clinicopathologic variables, and plasma and urine amino acid (AA) profiles among ACHES cases by skin lesion status. ANIMALS: Dogs of various breeds and ages diagnosed with ACHES (n = 41). A control (CON) cohort (n = 12) provided AA profile data. METHODS: Retrospective case series. Available medical records of previously identified cases were reviewed for salient clinical features and clinical pathology data. Plasma and urine AA profiles were performed. Cutaneous lesion status was classified as none, mild, or fulminant. RESULTS: Thirty cases (73%) developed SND at some time. Dogs with fulminant skin lesions at diagnosis (n = 22/41, 54%) had significantly lower hematocrit (P = .05) and mean corpuscular volume (P = .01) than dogs without SND. Principal component analysis of plasma AA profiles identified distinct clustering of CON from ACHES dogs, but not by skin lesion status. Plasma 1-methylhistidine (<7 nmol/mL) and cystathionine (<7.5 nmol/mL) were robust ACHES biomarkers. Urine lysine (>344 nmol/mg creatinine) and methionine (>68 nmol/mg creatinine) also were useful ACHES biomarkers. CONCLUSIONS AND CLINICAL IMPORTANCE: Specific AA biomarkers provide additional diagnostic utility in ACHES. Data suggests that HCH is an early stage, and SND a later stage manifestation of ACHES.

Treatment and outcomes of dogs with hepatocutaneous syndrome or hepatocutaneous-associated hepatopathy.

BACKGROUND: Superficial necrolytic dermatitis (SND) in dogs is a rare disorder most commonly associated with hepatocutaneous syndrome. Although often reported as fatal, sporadically reported long-term remissions might be more common than previously believed and linked to treatment regimens. HYPOTHESIS/OBJECTIVES: Evaluate treatments and associated outcomes in dogs with hepatocutaneous-associated hepatopathy (HCH) with or without SND, designated collectively aminoaciduric canine hypoaminoacidemic hepatopathy syndrome (ACHES). ANIMALS: Forty-one dogs of various breeds and ages diagnosed with ACHES. METHODS: Retrospective study. Electronic surveys, medical records (2014-2019), and communication with veterinarians provided data. Three treatment categories were each dichotomized: IV amino acid (IV-AA) infusions (≥2 vs <2), supplements including S-adenosylmethionine (SAMe), arginine with ornithine, glutathione, lysine, proline, omega-3 fatty acids, or zinc (≥3 vs <3), and diet type (home-cooked vs commercial). Optimal treatment was defined as receiving ≥2 IV-AA treatments, ≥3 nutritional supplements, and a home-cooked diet. RESULTS: Most dogs (29/41, 71%) received IV-AA infusions (23/29, ≥2 infusions). Twenty-one dogs (51%) were fed commercial diets; 17/41 (41%) were fed home-cooked diets. Most dogs received SAMe (32/41, 78%) and a median of 3 supplements. In 4 dogs, HCH remission occurred. Overall all-cause median survival time (MST) was 359 days, and disease-specific MST was 557 days (range, 1-1783 days). Optimally treated dogs (n = 9) lived significantly longer (MST, >1783 days, P = .02) than variably treated dogs (MST, 214 days). CONCLUSIONS AND CLINICAL IMPORTANCE: Optimized ACHES management can resolve SND and HCH and confer long-term survival.

Variant-specific and reciprocal Hsp40 functions in Hsp104-mediated prion elimination.

The amyloid-based prions of Saccharomyces cerevisiae are heritable aggregates of misfolded proteins, passed to daughter cells following fragmentation by molecular chaperones including the J-protein Sis1, Hsp70 and Hsp104. Overexpression of Hsp104 efficiently cures cell populations of the prion [PSI+ ] by an alternative Sis1-dependent mechanism that is currently the subject of significant debate. Here, we broadly investigate the role of J-proteins in this process by determining the impact of amyloid polymorphisms (prion variants) on the ability of well-studied Sis1 constructs to compensate for Sis1 and ask whether any other S. cerevisiae cytosolic J-proteins are also required for this process. Our comprehensive screen, examining all 13 members of the yeast cytosolic/nuclear J-protein complement, uncovered significant variant-dependent genetic evidence for a role of Apj1 (antiprion DnaJ) in this process. For strong, but not weak [PSI+ ] variants, depletion of Apj1 inhibits Hsp104-mediated curing. Overexpression of either Apj1 or Sis1 enhances curing, while overexpression of Ydj1 completely blocks it. We also demonstrated that Sis1 was the only J-protein necessary for the propagation of at least two weak [PSI+ ] variants and no J-protein alteration, or even combination of alterations, affected the curing of weak [PSI+ ] variants, suggesting the possibility of biochemically distinct, variant-specific Hsp104-mediated curing mechanisms.

Immune challenges decrease biliverdin concentration in the spleen of northern Bobwhite quail, Colinus virginianus.

Most antioxidants have multiple functions; in addition to minimizing oxidative damage, many antioxidants have immune-modulating properties. For example, biliverdin is produced in the liver and spleen from the breakdown of heme, and has putative immune-suppressing and antioxidant properties. However, the majority of these properties have been investigated in vitro or in mammalian models, in which biliverdin reductase converts virtually all biliverdin to bilirubin. Thus, biliverdin's physiological roles remain largely untested. Here, we investigated whether biliverdin has immunomodulating roles by injecting Northern Bobwhite quail (Colinus virginianus) with either a vehicle control, lysed and rinsed pig red blood cells (pRBC) that contain erythrocyte antigens but no heme, or intact pRBC that contain both erythrocyte antigens and hemoglobin, thus increasing the amount of heme that can be converted to biliverdin. We then quantified hemagglutination and hemolysis ability, and biliverdin concentration in the liver and spleen, on 3, 6, and 9 days post-injection. We found that hemagglutination was greater in individuals that received intact pRBC, but not in those injected with heme-removed pRBC, demonstrating that biliverdin does not suppress immune function at this dosage. Biliverdin levels of liver and spleen were correlated within individuals, suggesting organism-level variation in biliverdin production. Lastly, individuals injected with intact pRBC had a reduced biliverdin concentration in the spleen, suggesting that immune challenges may reduce biliverdin production or accumulation. This initial investigation demonstrated that biliverdin may have more nuanced physiological roles than previously reported, supporting the value of further investigations into the physiology of biliverdin.