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Babesia species infect a very wide range of mammal hosts across the globe, and zoonotic infections are of growing concern. Several species of the Babesia genus infect dogs, and some of these cause significant morbidity and mortality. The Apicomplexan parasite resides within the red cell and infections result in direct damage to the host through intra- and extravascular hemolysis. An exuberant inflammatory response by the host to some species of Babesia parasites also results in significant collateral damage to the host. Canine infections have been the subject of many studies as the well-being of these companion animals is increasingly threatened by the spread of tick vectors and an increasingly mobile dog population. There are currently no widely available and effective vaccines, and effective treatment can be challenging. Understanding disease pathogenesis underlies the development of new treatments. The varying pathogenicity of the various Babesia parasite species that infect dogs offers an opportunity to explore the molecular basis for the wide range of diseases caused by infection with this parasite genus. In this review, we focus on what has been reported about the clinical presentation of Babesia-infected dogs in an attempt to compare the severity of disease caused by different Babesia species.

Abstract Background The control of tick and flea burdens in dogs and cats has become essential to the control of important and emerging vector borne diseases, some of which are zoonoses. Flea worry and flea bite hypersensitivity are additionally a significant disease entity in dogs and cats. Owner compliance in maintaining the pressure of control measures has been shown to be poor. For these reasons efforts are continuously being made to develop ectoparasiticides and application methods that are safe, effective and easy to apply for pet owners. A new polymer matrix collar has recently been developed which is registered for 8 months use in cats and dogs. The basic properties of this collar have been investigated in several in vitro and in vivo studies. Methods The effects of imidacloprid, flumethrin and the combination were evaluated in vitro by means of whole cell voltage clamp measurement experiments conducted on isolated neuron cells from Spodoptera frugiperda. The in vitro efficacy of the two compounds and the combination against three species of ticks and their life stages and fleas were evaluated in a dry surface glass vial assay. The kinetics of the compounds over time in the collar were evaluated by the change in mass of the collar and measurement of the surface concentrations and concentrations of the actives in the collar matrix by HPLC. Hair clipped from collar treated dogs and cats, collected at various time points, was used to assess the acaricidal efficacy of the actives ex vivo. Results An in vitro isolated insect nerve model demonstrated the synergistic neurotoxic effects of the pyrethroid flumethrin and the neonicotinoid imidacloprid. An in vitro glass vial efficacy and mortality study against various life stages of the ticks Ixodes ricinus, Rhipicephalus sanguineus and Dermacentor reticulatus and against the flea (Ctenocephalides felis) demonstrated that the combination of these products was highly effective against these parasites. The release kinetics of these actives from a neck collar (compounded with 10% imidacloprid and 4.5% flumethrin) was extensively studied in dogs and cats under laboratory and field conditions. Acaricidal concentrations of the actives were found to be consistently released from the collar matrix for 8 months. None of the collar studies in dogs or cats were associated with any significant collar related adverse event. Conclusion Here we demonstrated the synergism between the pyrethroid flumethrin and the neonicotinoid imidacloprid, both provided in therapeutically relevant doses by a slow release collar matrix system over 8 months. This collar is therefore a convenient and safe tool for a long-term protection against ectoparasites.

Abstract Background It has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced in females. The existence of these effects, and any implications for the development of vaccines and the design of vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the RCT and a nested case–control study to test this hypothesis. Methods Randomised controlled trial with a nested case–control study. Discussion We expect that, among the placebo group, males will have higher mortality caused by higher pathogen loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs of non-live vaccines in high-mortality populations.

Babesia species infect a very wide range of mammal hosts across the globe, and zoonotic infections are of growing concern. Several species of the Babesia genus infect dogs, and some of these cause significant morbidity and mortality. The Apicomplexan parasite resides within the red cell and infections result in direct damage to the host through intra- and extravascular hemolysis. An exuberant inflammatory response by the host to some species of Babesia parasites also results in significant collateral damage to the host. Canine infections have been the subject of many studies as the well-being of these companion animals is increasingly threatened by the spread of tick vectors and an increasingly mobile dog population. There are currently no widely available and effective vaccines, and effective treatment can be challenging. Understanding disease pathogenesis underlies the development of new treatments. The varying pathogenicity of the various Babesia parasite species that infect dogs offers an opportunity to explore the molecular basis for the wide range of diseases caused by infection with this parasite genus. In this review, we focus on what has been reported about the clinical presentation of Babesia-infected dogs in an attempt to compare the severity of disease caused by different Babesia species.

Babesia rossi causes severe morbidity and mortality in dogs in sub-Saharan Africa. This was an experimental study designed to observe systemic changes caused by Babesia rossi infection within a canine disease model as well as investigate the influence of inoculum dose and treatment on the progression of inflammation and clinical disease. Six healthy male beagle dogs formed the study population, one dog was splenectomised and used to raise the infectious inoculum, three were administered a high B. rossi infectious dose and two a low infectious dose. Clinical examination, complete blood count (CBC) and C-reactive protein (CRP) were determined daily. Cytokines were quantified on stored plasma collected during the study, using a canine specific cytokine magnetic bead panel (Milliplex©). The experiment was terminated, and treatment administered once predetermined experimental or humane endpoints were reached. The data and information provided in the following article is the summary of all data points collected over the course of the eight-day experimental infection.

Abstract Background Babesia rossi is a leading cause of morbidity and mortality among the canine population of sub-Saharan Africa, but pathogenesis remains poorly understood. Previous studies of B. rossi infection were derived from clinical cases, in which neither the onset of infection nor the infectious inoculum was known. Here, we performed controlled B. rossi inoculations in canines and evaluated disease progression through clinical tests and whole blood transcriptomic profiling. Results Two subjects were administered a low inoculum (104 parasites) while three received a high (108 parasites). Subjects were monitored for 8 consecutive days; anti-parasite treatment with diminazene aceturate was administered on day 4. Blood was drawn prior to inoculation as well as every experimental day for assessment of clinical parameters and transcriptomic profiles. The model recapitulated natural disease manifestations including anemia, acidosis, inflammation and behavioral changes. Rate of disease onset and clinical severity were proportional to the inoculum. To analyze the temporal dynamics of the transcriptomic host response, we sequenced mRNA extracted from whole blood drawn on days 0, 1, 3, 4, 6, and 8. Differential gene expression, hierarchical clustering, and pathway enrichment analyses identified genes and pathways involved in response to hemolysis, metabolic changes, and several arms of the immune response including innate immunity, adaptive immunity, and response to viral infection. Conclusions This work comprehensively characterizes the clinical and transcriptomic progression of B. rossi infection in canines, thus establishing a large mammalian model of severe hemoprotozoal disease to facilitate the study of host-parasite biology and in which to test novel anti-disease therapeutics. The knowledge gained from the study of B. rossi in canines will not only improve our understanding of this emerging infectious disease threat in domestic dogs, but also provide insight into the pathobiology of human diseases caused by Babesia and Plasmodium species.

This paper seeks to measure the extent to which algorithmically generated playlists, conceptualised herein as cultural intermediaries (Bourdieu 1984), create ‘attachment’ between consumers of music and producers of music. This was undertaken following debates in the professional music press problematising the ability of streaming platforms to create relationships between artists and listeners and, in a wider discussion, to generate sustainable income for musicians (Chartmetric 2018, Mulligan 2019 in Griffiths 2019, Music Ally 2019). We develop the idea from cultural and economic scholars that intermediation results in ‘attachment’ on behalf of consumers (Callon et.al 2002, Smith Maguire & Matthews 2012) by formulating a definition of the term informed by insights from consumer psychology and applying this framework to a 115-question survey completed by listeners to Spotify’s ‘Discover Weekly’ Playlist for a one-week period. The findings suggest that the playlist was able to generate close to no attachment for those considered poorly-involved new music consumers, and only minor to mid-levels of attachment for those participants considered heavily-involved new music consumers. We therefore propose that algorithmically curated playlists can influence low-cost audience attachment behaviours while their overall impact on the economic success of artists may be limited. This paper contributes towards academic debates concerning the role and impact of cultural intermediaries and lends early empirical support to discussions within the professional music industries and wider public policy (GOV 2020) concerning the uncertain ability of playlists to influence the artist-fan relationship. In addition, by developing a methodologically precise definition of ‘attachment’, it is hoped that the framework provided by this modest study can act as a guide for other researchers to explore the concept of intermediation and attachment with larger sample sizes on alternative playlist types and on other digital platforms.

Abstract Background The strong ion model (SIM) is an alternative paradigm in the characterization of acid‐base disturbances particularly in complex disorders. Hypothesis/Objectives To compare the acid‐base changes in dogs with parvoviral enteritis (PE) using the Henderson‐Hasselbalch (HH) approach, with 2 strong ion approaches. Animals Forty‐four dogs with PE, and 16 age‐matched control dogs. Methods Prospective controlled observational study. Acid‐base status was evaluated using the HH model, Fencl‐Stewart (FS) approach and a validated strong ion model (VDM). The acid‐base changes according to each model were classified and compared. Statistical correlations between pH, CO2, and various SIM variables were performed, as well as between the sum of effects (SOE) of the SIM and the individual variables comprising the SOE. Results The HH model identified acid‐base disorders in 31/44 cases of which 16/31 were mixed with metabolic acidosis and concurrent respiratory alkalosis the most common (10/31). Using the FS approach, metabolic changes were present 36/42 cases, with changes in free water (FW), chloride, and unmeasured anions (UA) being the most prevalent. Both FW and UA correlated well with pH; however, UA were most consistently abnormal in severe acidemia. Similarly to the HH, the VDM detected acid‐base disturbances in 28/44 cases. Major contributors to the acid‐base changes were hyponatremia, hypochloremia, and Atot acidosis because of elevated globulins and increased UA. Conclusions and Clinical Importance Acid‐base changes are common and complex in dogs with PE, and were easier to understand using a SIM paradigm. Increases in UA have not been documented in PE in dogs.

In 2021, a pregnant Rottweiler dog living on a sheep farm was diagnosed with clinical bluetongue (BT) infection. This study reports on the investigation of this farm where bluetongue virus (BTV) infection was diagnosed in this atypical host species. Samples were collected during farm visits 14, 28, 60, and 89 days after the onset of clinical signs in the pregnant Rottweiler. Blood was collected from all farm dogs (n = 6) and tested for BTV genome using a reverse‐transcriptase quantitative PCR (RT‐qPCR) assay and BTV antibodies with the competitive ELISA (cELISA) and dogs positive by RT‐qPCR were further tested using virus neutralization (VN) serological testing. Blood was also collected from 16 sick sheep and tested using RT‐qPCR. Midges were trapped on the study farm using an Onderstepoort UV light trap placed above a sheep pen for 36 hr at the first farm (14 days) visit. Parous/gravid midges were tested by BTV RT‐qPCR in batches of up to 200 midges per species. Blood‐fed midges (n = 308) were tested using a PCR species probe (KAPA Multiplex Master Mix) to identify the host species on which the midge had fed. Three dogs (n = 3/6) had detectable BTV RNA with RT‐qPCR and high VN antibody titers to BTV. All RT‐qPCR‐positive dogs and one additional dog tested cELISA seropositive (n = 4/6). Bluetongue virus RNA was detected in 5/16 sheep tested. The most abundant midge species was Culicoides imicola (99.3%) and BTV was only detected in this species (n = 3/4 batches of 200 parous midges). Dog blood was not detected in any blood‐fed midges tested. The occurrence of natural BT viraemia in exposed dogs creates a potential risk of BTV entry into BT‐free countries through dog importation. It remains unclear whether BT viremia in dogs is capable of onward transmission. [ABSTRACT FROM AUTHOR]

To achieve global elimination of human rabies from dogs by 2030, evidence-based strategies for effective dog vaccination are needed. Current guidelines recommend inclusion of dogs younger than 3 months in mass rabies vaccination campaigns, although available vaccines are only recommended for use by manufacturers in older dogs, ostensibly due to concerns over interference of maternally-acquired immunity with immune response to the vaccine. Adverse effects of vaccination in this age group of dogs have also not been adequately assessed under field conditions. In a single-site, owner-blinded, randomized, placebo-controlled trial in puppies born to mothers vaccinated within the previous 18 months in a high-mortality population of owned, free-roaming dogs in South Africa, we assessed immunogenicity and effect on survival to all causes of mortality of a single dose of rabies vaccine administered at 6 weeks of age. We found that puppies did not have appreciable levels of maternally-derived antibodies at 6 weeks of age (geometric mean titer 0.065 IU/mL, 95% CI 0.061−0.069; n = 346), and that 88% (95% CI 80.7−93.3) of puppies vaccinated at 6 weeks had titers ≥0.5 IU/mL 21 days later (n = 117). Although the average effect of vaccination on survival was not statistically significant (hazard ratio [HR] 1.35, 95% CI 0.83−2.18), this effect was modified by sex (p = 0.02), with the HR in females 3.09 (95% CI 1.24−7.69) and the HR in males 0.79 (95% CI 0.41−1.53). We speculate that this effect is related to the observed survival advantage that females had over males in the unvaccinated group (HR 0.27; 95% CI 0.11−0.70), with vaccination eroding this advantage through as-yet-unknown mechanisms.

Background: The regenerative response following Babesia rossi infection in dogs is mild, despite severe hemolytic anemia. Objective: We aimed to compare the admission absolute reticulocyte count (ARC) and reticulocyte indices in 103 dogs naturally infected with B. rossi with 10 dogs suffering from immune‐mediated hemolytic anemia (IMHA) and 14 healthy control dogs. The regenerative response was also evaluated in five dogs experimentally infected with B. rossi. Methods: This is a retrospective observational study of records generated on the ADVIA 2120 hematology analyzer. Results: The median hematocrits (HCT) of the B. rossi and IMHA groups were significantly lower than the control group (p <.001 for both); however, no differences were seen between the B. rossi and IMHA groups. Compared with the control group, the median ARC was significantly higher in the B. rossi (p =.006) and IMHA (p =.019) groups but significantly lower in the B. rossi group than the IMHA group (p =.041). In the experimentally infected dogs, there was a sudden decrease in the ARC approximately 48 h after the detection of peripheral parasitemia, which was followed by an increase after treatment. Reticulocytes of naturally infected B. rossi dogs were larger, with more variation in cellular volume. The reticulocytes of the experimentally infected dogs decreased in size with decreasing hemoglobin concentrations as the study progressed. Conclusions: The regenerative response in dogs naturally infected with B. rossi is inadequate, given the severity of the anemia observed, and it might be a result of direct suppressive action by the parasite or host response on the bone marrow. [ABSTRACT FROM AUTHOR]

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Acute myeloid leukemia (AML) has a high mortality rate despite chemotherapy and transplantation. Both CXCR4/SDF-1 and VLA-4/VCAM1 axes are involved in leukemia protection but little is known about the role of CCL2/CCR2 in AML biology and protection against chemotherapy. We measured CCR2 expression in AML cell lines and primary AML cells by flow cytometry (FCM), real time PCR (RT-PCR) and western blot (WB). CCL2 production was quantified by solid phase ELISA in peripheral blood (PB) and bone marrow (BM) serum. We measured chemotaxis in a transwell system with different concentrations of CCL2/CCR2 blockers; cell cycle with BrDU and propidium iodide and proliferation with yellow tetrazolium MTT. We determined synergy in in vitro cell apoptosis combining chemotherapy and CCL2/CCR2 blockade. Finally, we performed chemoprotection studies in an in vivo mouse model. Of 35 patients, 23 (65%) expressed CCR2 by FCM in PB. Two cell lines expressed high levels of CCR2 (THP-1 and murine AML). RT-PCR and WB confirmed CCR2 production. CCL2 solid phase ELISA showed significantly lower levels of CCL2 in PB and BM compared to normal controls. Chemotaxis experiments confirmed a dose-dependent migration in AML primary cells expressing CCR2 and THP-1 cells. A significant inhibition of transmigration was seen after CCL2/CCR2 blockade. Proliferation of CCR2+ AML cell lines was slightly increased (1.4-fold) after axis stimulation. We observed a non-significant increase in phase S THP-1 cells exposed to CCL2 and a concomitant decrease of cells in G1. The chemotherapy studies did not show a protective effect of CCL2 on cytarabine-induced apoptosis or synergy with chemotherapy after CCL2/CCR2 blockade both in vitro and in vivo. In conclusion, CCL2/CCR2 axis is expressed in the majority of monocytoid AML blasts. The axis is involved in cell trafficking and proliferation but no in vitro and in vivo chemotherapy protective effect was seen.