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Nonprimate hepacivirus (NPHV) is the closest known relative of hepatitis C virus (HCV) and its study could enrich our understanding of HCV evolution, immunity, and pathogenesis. High seropositivity is found in horses worldwide with ∼3% viremic. NPHV natural history and molecular virology remain largely unexplored, however. Here, we show that NPHV, like HCV, can cause persistent infection for over a decade, with high titers and negative strand RNA in the liver. NPHV is a near-universal contaminant of commercial horse sera for cell culture. The complete NPHV 3′-UTR was determined and consists of interspersed homopolymer tracts and an HCV-like 3′-terminal poly(U)-X-tail. NPHV translation is stimulated by miR-122 and the 3′-UTR and, similar to HCV, the NPHV NS3-4A protease can cleave mitochondrial antiviral-signaling protein to inactivate the retinoic acid-inducible gene I pathway. Using an NPHV consensus cDNA clone, replication was not observed in primary equine fetal liver cultures or after electroporation of selectable replicons. However, intrahepatic RNA inoculation of a horse initiated infection, yielding high RNA titers in the serum and liver. Delayed seroconversion, slightly elevated circulating liver enzymes and mild hepatitis was observed, followed by viral clearance. This establishes themolecular components of a functional NPHV genome. Thus, NPHV appears to resemble HCV not only in genome structure but also in its ability to establish chronic infection with delayed seroconversion and hepatitis. This NPHV infectious clone and resulting acute phase sera will facilitate more detailed studies on the natural history, pathogenesis, and immunity of this novel hepacivirus in its natural host.

Equine type 1 polysaccharide storage myopathy (PSSM1), a common glycogenosis associated with an R309H founder mutation in the glycogen synthase 1 gene (GYS1), shares pathological features with several human myopathies. In common with related human disorders, the pathogenesis remains unclear in particular, the marked phenotypic variability between affected animals. Given that affected animals accumulate glycogen and alpha-crystalline polysaccharide within their muscles, it is possible that physical disruption associated with the presence of this material could exacerbate the phenotype. The aim of this study was to compare the histopathological changes in horses with PSSM1, and specifically, to investigate the hypothesis that the severity of underlying pathology, (e.g. vacuolation and inclusion formation) would (1) be higher in homozygotes than heterozygotes and (2) correlate with clinical severity. Resting and post-exercise plasma creatine kinase (CK) and aspartate aminotransferase (AST) enzyme activity measurements and muscle pathology were assessed in matched cohorts of PSSM1 homozygotes, heterozygotes or control horses. Median (interquartile range (IR)) resting CK activities were 364 (332-764) U/L for homozygotes, 301 (222-377) U/L for heterozygotes and 260 (216-320) U/L for controls, and mean (+/- SD) AST activity for homozygotes were 502 (+/116) U/L, for heterozygotes, 357 (+/-92) U/L and for controls, 311 (+/-64) U/L and were significantly different between groups (P = 0.04 and P = 0.01 respectively). Resting plasma AST activity was significantly associated with the severity of subsarcolemmal vacuolation (rho = 0.816; P = 0.01) and cytoplasmic inclusions (rho = 0.766; P = 0.01). There were fewer type 2× and more type 2a muscle fibres in PSSM1-affected horses. Our results indicate that PSSM1 has incomplete dominance. Furthermore, the association between plasma muscle enzyme activity and severity of underlying pathology suggests that physical disruption of myofibres may contribute to the myopathic phenotype. This work provides insight into PSSM1 pathogenesis and has implications for related human glycogenoses.

In this study, equine source polyclonal anti- Bacillus anthracis immunoglobulins were generated and utilized to demonstrate passive protection of mice in a lethal challenge assay. Four horses were hyper-immunized with B. anthracis Sterne strain for approximately one year. The geometric mean anti-PA titer in the horses at maximal response following immunization was 1:77,936 (Log2 mean titer 16.25, SEM ± 0.25 95% CI [15.5 –17.0]). The geometric mean neutralizing titer at maximal response was 1:128 (Log2 mean titer 7, SEM ± 0.0, 95% CI 7). Treatment with hyper-immune plasma or purified immunoglobulins was successful in passively protecting A/J mice from a lethal B. anthracis Sterne strain challenge. The treatment of mice with hyper-immune plasma at time 0 h and 24 h post-infection had no effect on survival, but did significantly increase mean time to death ( p  < 0.0001). Mice treated with purified immunoglobulins at time 0 h and 24 h post-infection in showed significant increase in survival rate ( p  < 0.001). Bacterial loads in lung, liver and spleen tissue were also assessed and were not significantly different in mice treated with hyper-immune plasma from placebo treated control mice. Mice treated with purified antibodies demonstrated mean colony forming units/gram tissue fourfold less than mice receiving placebo treatment ( p  < 0.0001). Immunotherapeutics harvested from horses immunized against B. anthracis Sterne strain represent a rapidly induced, inexpensive and effective expansion to the arsenal of treatments against anthrax.

ObjectiveAs biologic augmentation methods emerge, objective measures of soft tissues are necessary for developmental study. The purpose of this study was to develop a quantitative MRI mapping protocol for the ACL. The objectives were (1) to provide age-based T2 relaxation, T2* relaxation, and volume values in healthy individuals, (2) to establish the intra-rater and inter-rater reliability of ACL mapping, and (3) to determine whether 3-T or 7-T MRI is more appropriate for future clinical trials.Materials and methodsThirty healthy participants, aged 18–62, asymptomatic for knee pathology and without history of knee injury underwent both a 3-T and 7-T MRI. Manual image mapping of the anterior cruciate ligament was performed by two observers and processed to obtain T2, T2*, and volume values. Analysis of variance and two-way random effects model were used to calculate statistical significance and intraclass correlation coefficients.ResultsAcross all participants, 3-T and 7-T mean T2, T2* and volume values were 37.1 ± 7.9 and 39.7 ± 6.2 ms (p = 0.124), 10.9 ± 1.3 and 10.9 ± 0.9 ms (p = 0.981), and 2380 ± 602 and 2484 ± 736 mm3 (p = 0.551), respectively. The T2, T2*, and volume did not vary between age cohorts (p > 0.05). Excellent inter-rater and intra-rater reliability regarding T2 and T2* values was found. While ACL volume exhibited good inter-rater reliability and excellent intra-rater reliability.ConclusionsT2 relaxation values and ACL volume do not vary with age and therefore can be used as a quantifiable, non-invasive method to assess ACL graft maturation. 7-T MRI analysis was not superior to 3-T MRI analysis, suggesting that 3-T MRI is practical and capable for future comparative studies.

The objective of this study was to compare the mRNA expression of Toll-like receptors (TLR3 and TLR7), and costimulatory molecules involved in activation of lymphocytes and antigen presenting cells (CD80, CD86, CD28, and CD40L) after experimental infection of beef calves with low or high virulence noncytopathic (ncp) bovine viral diarrhea virus (BVDV) strains. Thirty BVDV-naïve, beef calves were intranasally inoculated with low (LV; n = 10, SD-1) or high (HV; n = 10, 1373) virulence ncp BVDV or with BVDV-free cell culture medium (Control, n = 10). Calves were euthanized on day 5 post-inoculation and tracheo-bronchial lymph node (TBLN) and spleen samples were collected for mRNA expression through quantitative-RT-PCR. Levels of mRNA for TLR3 and TLR7 were increased in spleen of HV group (P < 0.05), but not in LV group, compared to the control group. Expression of CD86 mRNA was up-regulated in TBLN of both LV and HV groups (P < 0.05). A significant up-regulation of CD80 mRNA was observed in TBLN for LV calves (P < 0.05), but not for HV calves. In conclusion, experimental inoculation with high virulence BVDV-2 1373 stimulated the expression of TLR3, TLR7 and CD86 in spleen and TBLN on day 5 post infection. In contrast, experimental challenge with the low virulence BVDV-1 SD-1 uniquely resulted in up-regulation of both CD80 and CD86 in TBLN samples on day 5 post infection. The observed differential expression during acute infection with high or low virulence BVDV might reflect differences in immune activation by these strains, which could be associated with differences in genotype and/or virulence.

The objectives of this research were to evaluate the risk of prolonged testicular infection as a consequence of vaccination of peri-pubertal bulls with a modified-live, noncytopathic strain of BVDV and to assess vaccine efficacy in preventing prolonged testicular infections after a subsequent acute infection. Seronegative, peri-pubertal bulls were vaccinated subcutaneously with an approximate minimum immunizing dose or a 10× standard dose of modified-live, noncytopathic BVDV or were maintained as unvaccinated controls. Forty-nine days after vaccination, all bulls were intranasally inoculated with a noncytopathic field strain of BVDV. Semen and testicular biopsies collected after vaccination and challenge were assayed for BVDV using virus isolation, reverse transcription-nested PCR, or immunohistochemistry and the identity of viral strains was determined by nucleotide sequencing of PCR products. The vaccine strain of BVDV was detected in testicular tissue of vaccinated bulls as long as 134 days after immunization. Prolonged testicular infections with the challenge strain were detected only in unvaccinated bulls as long as 85 days after challenge. Whereas vaccination caused prolonged testicular infection in some bulls, it did prevent subsequent infection of testicular tissue with the challenge strain. This research demonstrates that subcutaneous vaccination of naïve, peri-pubertal bulls with a noncytopathic, modified-live strain of BVDV can result in prolonged viral replication within testicular tissue. The risk for these prolonged testicular infections to cause venereal transmission of BVDV or subfertility is likely to be low but requires further investigation.