A novel, blocking, Fc-silent anti-CD40 monoclonal antibody prolongs nonhuman primate renal allograft survival in the absence of B cell depletion.

CD40-CD154 pathway blockade prolongs renal allograft survival in nonhuman primates (NHPs). However, antibodies targeting CD154 were associated with an increased incidence of thromboembolic complications. Antibodies targeting CD40 prolong renal allograft survival in NHPs without thromboembolic events but with accompanying B cell depletion, raising the question of the relative contribution of B cell depletion to the efficacy of anti-CD40 blockade. Here, we investigated whether fully silencing Fc effector functions of an anti-CD40 antibody can still promote graft survival. The parent anti-CD40 monoclonal antibody HCD122 prolonged allograft survival in MHC-mismatched cynomolgus monkey renal allograft transplantation (52, 22, and 24 days) with accompanying B cell depletion. Fc-silencing yielded CFZ533, an antibody incapable of B cell depletion but still able to potently inhibit CD40 pathway activation. CFZ533 prolonged allograft survival and function up to a defined protocol endpoint of 98-100 days (100, 100, 100, 98, and 76 days) in the absence of B cell depletion and preservation of good histological graft morphology. CFZ533 was well-tolerated, with no evidence of thromboembolic events or CD40 pathway activation and suppressed a gene signature associated with acute rejection. Thus, use of the Fc-silent anti-CD40 antibody CFZ533 appears to be an attractive approach for preventing solid organ transplant rejection.

Transapical balloon dilation of cor triatriatum sinister in a cat.

A hybrid surgical approach was utilized to address cor triatriatum sinister in a 10-month-old castrated male domestic shorthair cat. Prior to surgery, open-mouth breathing occurred with exertion. The procedure was guided by transesophageal echocardiography and fluoroscopy. A minithoracotomy was performed, and the left atrial membrane was accessed via an introducer placed through the left ventricular apex. Sequential balloon dilations were performed, and the mean transmembrane gradient under anesthesia was reduced from 16 mmHg to 2.23 mmHg. Four months after surgery, the transmembrane mean gradient remained lower than prior to intervention. The cat tolerated surgery well and remains free of clinical signs nine months after surgery.

Dilated cardiomyopathy of possible dietary origin in a cat.

An 11-year-old spayed female domestic shorthaired cat was diagnosed with severe dilated cardiomyopathy (DCM) and congestive heart failure. The cat had been eating cat foods that were high in pulses (e.g. peas, lentils, chickpeas). Neither plasma nor whole blood taurine concentrations were deficient. Primary treatment included furosemide, pimobendan, and clopidogrel, and changing to diets that did not contain pulses (a taurine supplements was not administered). The cat's clinical signs improved, high-sensitivity cardiac troponin I concentrations decreased, and echocardiographic measurements stayed relatively stable for over one year after initiating cardiac medications and changing the diet. Ultimately, the cat was euthanized for worsening congestive heart failure 374 days after the diagnosis of DCM. Infectious disease testing during the time of clinical surveillance was negative. Routine histopathology of the heart was unremarkable, but electron microscopy of the left ventricle showed large numbers of mitochondria of variable size and structure. A moderate number of lamellar bodies and autophagic vacuoles also were noted. This case report illustrates an unusual case of a cat with DCM unrelated to taurine deficiency. The relative roles of diet change, cardiac medications, and a dedicated owner are unclear, but this cat's relatively long survival time is similar to that seen after diet change in dogs and cats with DCM eating high-pulse diets.

Hypereosinophilic syndrome with cardiac infiltration and congestive heart failure in a cat.

Hypereosinophilic syndrome is an uncommon disorder in the cat. It is a heterogeneous group of conditions defined by a persistent hypereosinophilia associated with organ damage directly attributable to tissue hypereosinophilia. A seven-year-old castrated domestic shorthair cat presented to the emergency service for dyspnea. Initial physical examination identified the presence of a grade III/VI systolic left parasternal murmur with no gallop or arrhythmia. A snap N-terminal-pro hormone brain natriuretic peptide was abnormal, and a point-of-care ultrasound revealed mild pleural effusion, scant pericardial effusion, and an enlarged left atrium. There was leukemia (72.35 K/uL, reference range 4.5-15.7 K/uL) predominated by eosinophilia (33.84 K/uL; reference range 0-1.9 K/uL). On echocardiogram, there was concentric hypertrophy of the left ventricular walls with irregular endocardial borders. The left atrium was enlarged with evidence of spontaneous echogenic contrast. The mitral valve was thickened with a vegetative lesion on the anterior leaflet. Despite treatment, the patient experienced cardiopulmonary arrest, and cardiopulmonary resuscitation was unsuccessful. Complete necropsy with histopathology revealed eosinophilic infiltrates in multiple organs and the presence of a severe, acute-on-chronic, fibrinous, and eosinophilic-granulomatous endomyocarditis with mural thrombosis and marked endocardial fibrosis. This case represents an unusual presentation of the hypereosinophilic syndrome in the cat with cardiac involvement and congestive heart failure as a primary clinical sign.

Clinical status and endoscopy of the upper respiratory tract of dairy calves infected with Bovine viral diarrhea virus 2 and Bovine herpes virus 1 after vaccination and trace minerals injection.

The objective was to compare clinical protection [evaluated through health scoring, endoscopy score of the upper respiratory tract (URT-ES), leukocyte count, viremia, and virus shedding in nasal secretions] following Bovine viral diarrhea virus 2 (BVDV2) and Bovine herpes virus 1 (BHV1) challenge among calves submitted to modified-live virus (MLV) booster vaccination (either intranasal or subcutaneous) concurrent with injectable trace minerals (ITM) or saline. Forty-eight dairy calves received an MLV intranasal (IN) vaccine containing BHV1, BRSV, and BPI3V and subcutaneous (SC) ITM (Se, Cu, Zn & Mn; ITM, n = 24) or saline (SAL, n = 24). Ten weeks later, calves received a second dose of ITM, or saline, according to previous groups and were randomly assigned to receive the same IN vaccine [ITM-IN (n = 12), SAL-IN (n = 12)] or a SC MLV vaccine containing BHV1, BRSV, BPI3V, BVDV1 & 2 [ITM-SC (n = 12), SAL-SC (n = 12)]. Additionally, 12 calves did not receive vaccine or treatment and served as a control group (UNVAC, n = 12). Forty-nine days after booster, calves were challenged with BVDV2; and seven days later with BHV1. Health scores indicated disease in UNVAC on days 6, 10 and 12 compared to the vaccinated groups. Unvaccinated calves had the highest URT-ES after BHV1 challenge. Calves that received SC booster had lower URT-ES after BHV1 challenge than UNVAC calves. Calves in ITM-IN had significantly lower URT-ES after BHV1 infection than SAL-IN and UNVAC calves. In conclusion, IN or SC MLV vaccination was similarly effective in protecting calves from BVDV2 + BHV1 challenges (reducing clinical and endoscopy scores, preventing leukopenia, and viremia), compared to unvaccinated calves. Endoscopic evaluation of the URT allowed visualization of the inflammation and damage at multiple depths in the URT caused by a serial BVDV2 + BHV1 challenge. Calves that received SC vaccination had significantly lower URT-ES after BHV1 challenge than the UNVAC calves. Administration of ITM concurrent with IN vaccination was associated with reduced URT inflammation after BVDV2 + BHV1 challenge.

Dilated cardiomyopathy in cats: survey of veterinary cardiologists and retrospective evaluation of a possible association with diet.

INTRODUCTION/OBJECTIVES: The objectives were to conduct a survey of cardiologists on their recent experiences with cats that have dilated cardiomyopathy (DCM) and to retrospectively review individual cases of feline DCM. ANIMALS, MATERIALS AND METHODS: Part one: A survey was distributed to cardiologists with questions regarding caseload and clinical management of cats with DCM diagnosed over the past two years. Part two: Cardiologists completing the survey were invited to submit data from cats recently diagnosed with DCM. Data on signalment, clinical signs, diet, echocardiographic measurements and outcome were recorded. RESULTS: Part one: From 52 completed surveys, many cardiologists responded that measuring and supplementing taurine and recommending a diet change in cats with DCM are common practices. Few (15%) cardiologists reported an increase in the number of feline DCM cases over the past two years, although some had cases that improved even if taurine deficiency was not present. Part two: Twenty of 37 (54%) cats ate low pea/lentil (low PL) diets, and 14/37 (38%) ate high PL diets at the time of diagnosis; three had incomplete diet information. Two of 13 cats (15%) in which taurine was measured had levels below the reference range. After adjusting for other variables, cats eating high PL diets that changed diets after diagnosis had a significantly longer survival time than that of cats eating high PL diets that did not change diets after diagnosis (P = 0.025). CONCLUSIONS: Additional research is warranted to determine whether there could be a possible association between diet and DCM in cats.

A neutron scattering study of hydrogen dynamics in coarse-grained and nanostructured ZrCr2H3.

The vibrational spectra of hydrogen and parameters of H diffusion in the coarse-grained C15-type system ZrCr(2)H(3) and in nanostructured ZrCr(2)H(3) have been studied by means of inelastic and quasielastic neutron scattering. It is found that the diffusive motion of hydrogen in coarse-grained ZrCr(2)H(3) can be described in terms of at least two jump processes: a fast localized H motion with the jump rate τ(l)( - 1) over the hexagons formed by interstitial Zr(2)Cr(2) sites and a slower process with the rate τ(d)( - 1) associated with H jumps leading to long-range diffusion. While τ(d)( - 1)(T) in the range 250-380 K follows the Arrhenius law with the activation energy of 142 ± 4 meV, the temperature dependence of τ(l)( - 1) deviates from Arrhenius behavior. The nanostructured ZrCr(2)H(3) samples prepared by ball milling consist of C15-type grains and strongly distorted (amorphous-like) regions. H atoms in the strongly distorted regions are found to be immobile on the time scale of our experiments. The microscopic picture of H jump motion in the C15-type grains of the nanostructured samples is similar to that in coarse-grained ZrCr(2)H(3); however, the ball milling leads to a considerable decrease in the jump rate τ(d)( - 1).

The relationship between body weight, body condition, and survival in cats with heart failure.

BACKGROUND: Obese people with heart failure have improved survival compared with their normal or underweight counterparts. The purpose of this study was to determine if there is a relationship between body weight or body condition and survival in cats with heart failure. HYPOTHESIS: Body weight and body condition score (BCS) are predictors of survival in cats with heart failure. ANIMALS: One-hundred and one cats with heart failure (International Small Animal Cardiac Health Council Classes II, IIIa, or IIIb) evaluated between March 2007 and June 2009. METHODS: Data regarding initial body weight and BCS, subsequent changes in body weight, and treatment were collected from records and compared with survival times. RESULTS: Median initial body weight was 5.1 kg (range, 2.2-9.5 kg). Median BCS was 5 (range, 3-9). Of the 68 cats that were discharged from the hospital, median body weight change was 0.0 kg (range, -2.6 to +2.3 kg). Survival time for all 101 cats was 93 days (0-811 days). Survival could be predicted using a model combining initial body weight (P=.02), body weight squared (P=.02), and survival to discharge (P<.001) with a resulting global P value for this model of P<.0001. CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with the lowest and highest body weights had reduced survival times compared with those with body weights in the intermediate ranges, suggesting a U-shaped relationship between body weight and survival. Additional research into the effects of body composition could help to determine optimal management of cats with heart failure.

Perceptions of quality of life and priorities of owners of cats with heart disease.

BACKGROUND: Owners' perceptions and priorities regarding quality of life (QoL) are important considerations given the unknown efficacy of many commonly administered medications, stress of hospital visits, difficulties providing home care, and personal choices including euthanasia. OBJECTIVE: To describe the relative importance of quality versus quantity of life to owners of cats with heart disease. ANIMALS: Two hundred and thirty-nine cats with heart disease. METHODS: Prospective questionnaire-based clinical study. Cat owners completed a questionnaire to identify important parameters when assessing their cat's QoL, the relative importance of quality versus quantity of life, and willingness to trade survival time for QoL. Variables associated with these parameters were evaluated with multivariate analyses. RESULTS: Appetite, owner interaction, sleep patterns, and litterbox habits were deemed important to QoL. Concern over pet suffering was significantly greater than concern over life expectancy. Ninety-three percent of owners were willing to trade survival time for good QoL; 57% of these were willing to trade up to 6 months. On multivariate analysis, the only factor significantly (P=.002) associated with willingness to trade 6 months was study site. Owner concern regarding stress of administering medications at home increased with number and frequency of medications. CONCLUSIONS AND CLINICAL RELEVANCE: These results indicated that QoL is more important to owners of cats with heart disease than longevity. The various priorities and concerns of cat owners should be taken into account in order to provide optimal care.

Primary cardiac hemangiosarcoma in a horse: echocardiographic and necropsy findings.

Cardiac hemangiosarcoma, especially primary, is infrequently reported in the horse and remains a diagnostic challenge because of vague clinical signs and difficulty to reach an antemortem diagnosis. A 17-year-old American Quarter Horse gelding was presented with a history of tongue swelling and secondary aspiration pneumonia. Initial assessment indicated dehydration, and thoracic ultrasound revealed an abnormal structure within the myocardium alongside the previously suspected aspiration pneumonia. A subsequent, complete echocardiogram identified a large, heterogeneous, ill-defined mass invading and replacing the normal myocardium of the right ventricular free wall. Because of lack of improvement the horse was euthanized, and postmortem examination confirmed primary cardiac hemangiosarcoma with no further masses identified in other organs. This case is an unusual presentation of primary cardiac hemangiosarcoma for which echocardiography played a significant role in identifying a cardiac mass.

Transmembrane movement of a water-soluble analogue of mannosylphosphoryldolichol is mediated by an endoplasmic reticulum protein.

Based on topological studies mannosylphosphoryldolichol (Man-P-Dol) is synthesized on the cytoplasmic face of the RER, but functions as a mannosyl donor in Glc3Man9GlcNAc2-P-P-dolichol biosynthesis after the mannosyl-phosphoryl headgroup diffuses transversely to the luminal compartment. The transport of mannosylphosphorylcitronellol (Man-P-Cit), a water-soluble analogue of Man-P-Dol, by microsomal vesicles from mouse liver, has been investigated as a potential experimental approach to determine if a membrane protein(s) mediates the transbilayer movement of Man-P-Dol. For these studies beta-[3H]Man-P-Cit was synthesized enzymatically with a partially purified preparation of Man-P-undecaprenol synthase from Micrococcus luteus. The uptake of the radiolabeled water-soluble analogue was found to be (a) time dependent; (b) stereoselective; (c) dependent on an intact permeability barrier; (d) saturable; (e) protease-sensitive; and (f) highest in ER-enriched vesicles relative to Golgi complex-enriched vesicles and intact mitochondria. Consistent with the involvement of a membrane protein, the analogue did not enter synthetic phosphatidylcholine-liposomes. [3H]Man-P-Cit also was not transported by human erythrocytes. These results indicate that the transport of Man-P-Cit by sealed microsomal vesicles from mouse liver is mediated by a membrane protein transport system. It is possible that the same membrane protein(s) participates in the transbilayer movement of Man-P-Dol in the ER.

Synchronous diaphragmatic contraction associated with dual-chamber transvenous pacing in a dog.

A 3-year-old, 20-kg, spayed female, mix-breed dog received a dual-chamber pacemaker for management of symptomatic 3rd-degree atrioventricular block. Synchronous diaphragmatic contraction was documented to occur with atrial pacing. Various methods to reduce the occurrence of pacemaker-related phrenic nerve stimulation are discussed.

Plasma growth differentiation factors 8 and 11 levels in cats with congestive heart failure secondary to hypertrophic cardiomyopathy.

OBJECTIVES: Growth differentiation factor (GDF) 11 has been shown to reduce cardiac hypertrophy in mice. Low levels of GDF-11 are associated with cardiac hypertrophy in humans. The authors hypothesized that plasma GDF-11 level is decreased in cats with hypertrophic cardiomyopathy (HCM). Given the close homology between GDF-11 and myostatin/GDF-8, GDF-8 levels were also assessed. ANIMALS: Thirty-seven client-owned cats were enrolled, including cats with normal cardiac structure (n = 16), cats with HCM or hypertrophic obstructive cardiomyopathy (HOCM; n = 14), and cats with HCM and congestive heart failure (CHF; n = 7). METHODS: Plasma samples were analyzed for GDF-8 and GDF-11 using liquid chromatography tandem-mass spectrometry. Levels of GDF-8 and GDF-11 were compared between cats with normal cardiac structure, HCM or HOCM, and CHF. RESULTS: No differences in GDF-11 concentrations were found between cats with normal cardiac structure and cats with HCM/HOCM, with or without history of CHF. Decreased GDF-8 concentrations were detected in cats with CHF compared to cats with HCM/HOCM without history of CHF (p=0.031) and cats with normal cardiac structure (p=0.027). Growth differentiation factor 8 was higher in cats with HOCM compared to those with CHF (p=0.002). No statistical difference was noted in GDF-8 level as a function of age, weight, or body condition score. CONCLUSIONS: Plasma GDF-11 was not different between cats with HCM/HOCM and cats with normal cardiac structure regardless of age. Plasma GDF-8 was decreased in cats with CHF compared to cats with normal cardiac structure and cats with asymptomatic HCM/HOCM, suggesting a possible role in CHF development.

Association of body weight and body condition with survival in dogs with heart failure.

BACKGROUND: Obesity is a risk factor for cardiovascular disease in people, but overweight and obese human heart failure patients have improved survival compared with normal--or underweight controls--the obesity paradox. The purpose of this study was to determine if there is an association of body weight and body condition with survival in dogs with heart failure. HYPOTHESIS: That body condition and changes in body weight are predictors of survival in dogs with heart failure. ANIMALS: One hundred and eight dogs with heart failure (International Small Animal Cardiac Health Council stages 2, 3a, or 3b) secondary to dilated cardiomyopathy or chronic valvular disease. METHODS: Medical records were reviewed, and data regarding initial body weight and body condition score (BCS), subsequent changes in body weight, and treatment were collected. Survival times were determined for dogs that were discharged from the hospital and lived >24 hours. RESULTS: Survival was significantly different between dogs that gained, lost, or maintained body weight over the course of their disease (P= .04), with dogs that gained weight surviving the longest. BCS and medications were not significantly associated with survival time; however, n-3 fatty acid intake was associated with longer survival time (P= .009). CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest that changes in body weight might be an important consideration in the survival of dogs with heart failure.

Echocardiographic ratio indices in overtly healthy Boxer dogs screened for heart disease.

BACKGROUND: Boxer dogs are routinely screened by echocardiography to exclude congenital and acquired heart disease. Individuals of a given breed may span a large range of body sizes, potentially invalidating linear regression of M-mode measurements against body weight. Echocardiographic ratio indices (ERIs) provide a novel method of characterizing echocardiographic differences between Boxers and other dog breeds. HYPOTHESIS: ERIs obtained from overtly healthy Boxer dogs presented for cardiac screening will be different from ERIs established for normal non-Boxer dogs, and those differences will be unrelated to aortic velocity or systolic blood pressure. ANIMALS: Eighty-one Boxers with no outward clinical signs of heart disease were studied. METHODS: All dogs were examined by 2-dimensional, M-mode, and Doppler echocardiography. M-mode measurements were used to perform ERI calculations, and the indices in Boxers were compared between Boxers with varying severity of arrhythmia and those of normal non-Boxer dogs. RESULTS: Differences in weight-based ERIs, which reflect increased thickness of the left ventricular free wall (LVW) and interventricular septum (IVS) and smaller aortic size, were found in overtly healthy Boxer dogs compared with normal non-Boxer dogs. ERIs of left atrial and LV cavity size in overtly healthy Boxers were not significantly different from those of non-Boxer dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Boxer dogs may have an increased relative thickness of the LVW and IVS that is independent of aortic size, aortic velocity, or arterial blood pressure, and this morphology should be taken into consideration when screening Boxers by echocardiography.

Hypercoagulability in cats with cardiomyopathy.

BACKGROUND: Arterial thromboembolism (ATE) is a common complication of feline cardiomyopathy; however, the pathogenesis of ATE is unknown. HYPOTHESIS: Systemic activation of the coagulation cascade (hypercoagulability) and endothelial injury promote ATE in cardiomyopathic cats. ANIMALS: Healthy cats (n = 30) and 3 groups of cardiomyopathic cats: Group (1) left atrial enlargement only (LAE [n = 11]), ie, left atrial to aortic ratio >1.4; Group (2) LAE with spontaneous echocardiographic contrast, atrial thrombi or both (SEC-T [n = 16]); and Group (3) acute ATE with LAE (n = 16). METHODS: Hypercoagulability was defined by 2 or more laboratory abnormalities reflecting coagulation factor excess (high fibrinogen concentration or Factor VIII coagulant activity), inhibitor deficiency (low antithrombin activity), or thrombin generation (high thrombin-antithrombin complex [TAT] and d-dimer concentrations). High von Willebrand factor antigen concentration (vWF : Ag) was considered a marker of endothelial injury. Data were analyzed using nonparametric statistics. RESULTS: The 3 groups of cats with cardiac disease had higher median fibrinogen concentrations than did the healthy cats. Criteria of hypercoagulability were found exclusively in cats with SEC-T (50%) and ATE (56%). Hypercoagulability was not associated with left atrial size or congestive heart failure (CHF). ATE cats had significantly higher median vWF : Ag concentration than did the other groups. CONCLUSION AND CLINICAL IMPORTANCE: Systemic hypercoagulability is evident in many cardiomyopathic cats, often without concurrent CHF or overt ATE. Hypercoagulabilty may represent a risk factor for ATE. High vWF : Ag in ATE cats was attributed to downstream endothelial injury from the occlusive thrombus.