Papers by Balazs Szladovits
Journal of Avian Medicine and Surgery, 2020
Abstract: Six adult Waldrapp ibis (Geronticus eremita) were presented with heavy metal toxicosis ... more Abstract: Six adult Waldrapp ibis (Geronticus eremita) were presented with heavy metal toxicosis secondary to paint chip ingestion after being placed in an indoor confinement enclosure because of a regional highly pathogenic avian influenza epornitic and government restrictions. Four of the ibis developed clinical disease signs between 45 and 64 days of confinement, including weakness, lethargy, inability to fly, low body condition, and bilateral wing droop while 2 birds appeared to remain normal during that period. Common clinicopathological findings included elevated plasma aspartate aminotransferase, creatine kinase, glutamate dehydrogenase, and bile acids values. Erythrocyte morphological changes included prominent hypochromasia, decreased size of polychromatophils with occasional cytoplasmic stippling, abnormal shapes, and D cells. Whole-body radiographic imaging revealed particulate radio-opaque material in the ventriculus of all affected birds. One bird died before chelation therapy could be instituted and heavy metal testing of the liver revealed increased concentrations of lead and zinc. Lead toxicosis was diagnosed in the 5 remaining birds by plasma lead analysis. These 5 birds were hospitalized for an average of 40 days and treated with sodium calcium edetate and fluid therapy, which resulted in resolution of the toxicosis. Plasma biochemistry, complete blood counts, and blood lead values were performed repeatedly on all 5 birds and were used to guide therapy and monitor treatment response. This case series emphasizes the importance of early contingency planning and reviews the treatment of lead toxicosis in birds with a focus on long-term clinical monitoring and hematology.
SummaryEpigenetics has hitherto been studied and understood largely at the level of individual or... more SummaryEpigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolutio...
Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic ... more Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species ...
ABSTRACTAging is often perceived as a degenerative process resulting from random accrual of cellu... more ABSTRACTAging is often perceived as a degenerative process resulting from random accrual of cellular damage over time. Despite this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, we hypothesized that one can build pan-mammalian clocks that measure age in all mammalian species. To address this, we generated data using 11,754 methylation arrays, each profiling up to 36 thousand cytosines in highly-conserved stretches of DNA, from 59 tissue-types derived from 185 mammalian species. From these methylation profiles, we constructed three age predictors, each with a single mathematical formula, termed universal pan-mammalian clocks that are accurate in estimating the age (r>0.96) of any mammalian tissue. Deviations between epigenetic age and chronological age relate to mortality risk in humans, mutations that...
ABSTRACTHuman DNA methylation profiles have been used successfully to develop highly accurate bio... more ABSTRACTHuman DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging (“epigenetic clocks”). Although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. This is exemplified by recent development of epigenetic clocks for mice and other mammalian species. Here, we describe epigenetic clocks for the domestic cat (Felis catus), based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs are measured using a custom-designed Infinium array (HorvathMammalMethylChip40). From these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. As the rate of human ep...
Journal of Zoo and Wildlife Medicine, 2020
Abstract: Population-based reference intervals (RIs) are vital tools used to characterize health ... more Abstract: Population-based reference intervals (RIs) are vital tools used to characterize health and disease based on laboratory values. The science and statistical basis for RI generation have evolved over the past 50 yr. Current veterinary-specific guidelines by the American Society of Veterinary Clinical Pathology exist for establishing RIs from nondomestic and wild animals. A list of 35 items that should be included during generation and publication of reference data was distilled from the currently available RI guidelines. The archives of five peer-reviewed journals were searched and 106 articles presenting laboratory reference data from nondomestic or wildlife species were identified and each reviewed by two authors to determine compliance with the list of 35 items. A compliance score was calculated as the number of articles that fulfilled the item out of the number where it would have been appropriate to fulfill the item. Most articles reported the number of reference individuals (compliance score 0.98), their partitioning demographics (compliance score 0.95), and sample collection and handling practices (compliance scores 0.97 and 0.96, respectively). Common deficiencies included omitting discussion of the validation status of the analytical methods for the species being evaluated (compliance score 0.12), documentation of use of exclusion criteria (compliance score 0.51), outlier detection (compliance score 0.43), appropriate statistical methods for the reference population (compliance score 0.34), and calculation and presentation of confidence intervals around the reference limits (compliance score 0.35). Compliance scores were not statistically different when stratified on the number of individuals in the largest and smallest evaluated group or the format of the article (full vs short format). Articles that cited RI generation guidelines fulfilled more of the required steps and provided a more complete description of their data (compliance score 0.74) than those that did not cite guidelines (compliance score 0.58). Additional attention to the science of and recommendations for RI generation is recommended to strengthen the utility of published data.
Frontiers in Oncology, 2020
Gene expression profiling has revealed molecular heterogeneity of diffuse large B cell lymphoma (... more Gene expression profiling has revealed molecular heterogeneity of diffuse large B cell lymphoma (DLBCL) in both humans and dogs. Two DLBCL subtypes based on cell of origin are generally recognized, germinal center B (GCB)-like and activated B cell (ABC)-like. A pilot study to characterize the transcriptomic phenotype of 11 dogs with multicentric BCL yielded two molecular subtypes distinguished on the basis of genes important in oxidative phosphorylation. We propose a metabolic classification of canine BCL that transcends cell of origin and shows parallels to a similar molecular phenotype in human DLBCL. We thus confirm the validity of this classification scheme across widely divergent mammalian taxa and add to the growing body of literature suggesting cellular and molecular similarities between human and canine non-Hodgkin lymphoma. Our data support a One Health approach to the study of DLBCL, including the advancement of novel therapies of relevance to both canine and human health.
Veterinary Record, 2019
MethodsA randomised non-blinded non-inferiority trial was conducted to determine whether treatmen... more MethodsA randomised non-blinded non-inferiority trial was conducted to determine whether treatment with an unfractionated regimen of oral prednisolone was inferior to a fractionated regimen for dogs with primary immune-mediated haemolytic anaemia. Dogs received the same total daily dose of prednisolone as unfractionated (group 1, starting at 4 mg/kg orally once daily) or fractionated (group 2, starting at 2 mg/kg orally twice daily) doses. Questionnaires were administered to owners to assess adverse effects and quality of life (QoL). End points included survival to eight weeks, and changes in QoL and clinicopathological parameters over time.ResultsThirty-nine dogs were enrolled in the study, of which 5 were withdrawn and 17 were assigned to each group. The number of cases recruited was insufficient to determine whether unfractionated treatment was inferior to fractionated. Total serum bilirubin decreased more rapidly in dogs in group 2, whereas polydipsia improved more rapidly in gr...
Veterinary Record, 2018
An increasing number of non-endemic vectorborne pathogens have been described in dogs imported to... more An increasing number of non-endemic vectorborne pathogens have been described in dogs imported to the UK in the past two decades. Recently, an outbreak of canine babesiosis in south-east England has raised veterinary awareness with regard to the impact of such diseases on the UK canine population. Canine hepatozoonosis, caused by Hepatozoon canis and transmitted by the ingestion of Rhipicephalus sanguineus ticks, is widespread in the Mediterranean basin. Herein we describe the first three molecularly confirmed clinical cases of canine hepatozoonosis in dogs imported into the UK. Veterinarians in the UK should be aware of H canis as a potential infection in imported dogs, especially in the face of the expanding distribution of R sanguineus ticks in Europe.
Journal of feline medicine and surgery, Jan 14, 2018
Objectives Feline intracranial abscessation or empyema is infrequently reported in the veterinary... more Objectives Feline intracranial abscessation or empyema is infrequently reported in the veterinary literature. To date, the largest study is based on a population of 19 cats with otogenic infection. The aim of this study was to review a larger population of cats with intracranial empyema from multiple aetiologies and document their signalment, imaging findings, treatment protocols (including medical and/or surgical management) and to compare outcomes. Methods Cases presenting to a single referral centre over a 10 year period with compatible history, neurological signs and imaging findings consistent with intracranial abscessation and empyema were reviewed retrospectively. Results Twenty-three cats met the inclusion criteria. Advanced imaging (CT and/or MRI) was performed in 22/23 cats; one case was diagnosed via ultrasound. Ten cases underwent medical and surgical management combined, 10 underwent solely medical management and three were euthanased at the time of diagnosis. Short-ter...
Journal of Feline Medicine and Surgery Open Reports, 2017
Case summary A 15-year-old female cat was presented for investigation of progressive behavioural ... more Case summary A 15-year-old female cat was presented for investigation of progressive behavioural changes, polyuria, polydipsia and periuria. An ovarian granulosa cell tumour was identified and the cat underwent therapeutic ovariohysterectomy (OHE). The cat’s clinical signs resolved, but 6 months later it was diagnosed as having an anaplastic astrocytoma and was euthanased. Serum anti-Müllerian hormone (AMH) concentration prior to OHE was increased vs a control group of entire and neutered female cats. Following OHE, serum AMH concentration decreased to <1% of the original value. Relevance and novel information Serum AMH measurement may represent a novel diagnostic and monitoring tool for functional ovarian neoplasms in cats.
Veterinary Immunology and Immunopathology, 2017
Tierarztliche Praxis. Ausgabe K, Kleintiere/Heimtiere, Jan 19, 2017
Leptin and ghrelin, two peptide hormones with antagonistic effects on satiety and energy balance,... more Leptin and ghrelin, two peptide hormones with antagonistic effects on satiety and energy balance, could be involved in the pathogenesis of weight loss and polyphagia in cats with hyperthyroidism. Leptin generally decreases appetite and increases energy expenditure, while ghrelin exerts the opposite effects. Leptin and ghrelin were measured in 42 client owned hyperthyroid cats with a body condition score (BCS) ≤ 5/9 before (T0) and 4 weeks after radioactive iodine treatment (RAIT) (T1). Dependent on the serum total thyroxine concentration concentration at T1, cats were sub-classified as still hyperthyroid (ht-ht) (n = 4), euthyroid (ht-eu) (n = 10) or hypothyroid (ht-hypo) (n = 28). Results were compared to those of 22 healthy, euthyroid control cats with a comparable BCS (≤ 5/9) and age (≥ 8 years) to hyperthyroid cats. At T0, there were no significant differences between hyperthyroid and control cats for leptin (p = 0.06) or ghrelin concentrations (p = 0.27). At T1, leptin signific...
PLOS ONE, 2016
The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic ... more The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species.
Journal of Veterinary Internal Medicine, 2015
Background: Cholecystocentesis can be part of the diagnostic workup of hepatobiliary disease in s... more Background: Cholecystocentesis can be part of the diagnostic workup of hepatobiliary disease in small animals, but literature on cytological evaluation of bile is scant. Objectives: To determine the diagnostic utility of cytological assessment of bile aspirates. Animals: Fifty-six and 78 client-owned dogs and cats, respectively, with bile collected by cholecystocentesis and submitted to our diagnostic laboratory between 1999 and 2014. Methods: Retrospective study describing cytological findings of bile, concurrent bacterial culture results, hematological and serum biochemical data, gallbladder biopsy results, as well as final diagnosis and complications after cholecystocentesis. Results: Infectious agents were found in 30% of canine and 22% of feline bile aspirates, and inflammation in 5% and 19% respectively. Presence of microorganisms was more often detected on cytological examination (24%) than by culture (21%). The most common bacterial isolates were Escherichia coli and Enterococcus spp., isolated from 14.8% and 6.7% of cultured samples respectively. Only increased canine pancreatic lipase immunoreactivity concentration (cPLI) was significantly associated with the presence of microorganisms, inflammatory cells, or both in bile. Clinically relevant complications of cholecystocentesis occurred in 2 dogs. The majority of the animals undergoing cholecystocentesis suffered from hepatic, pancreatic, gastrointestinal disease, or a combination thereof. Conclusions and Clinical Importance: Cytological examination of bile is inexpensive and straightforward, and yields diagnostically relevant information that precedes and complements bacterial culture.
Veterinary Clinics of North America: Small Animal Practice, 2003
Leukocytosis is an increased leukocyte concentration in a sample collected from the circulating b... more Leukocytosis is an increased leukocyte concentration in a sample collected from the circulating blood pool. Leukocytosis results from changes in production, distribution, or use of neutrophils, lymphocytes, monocytes, eosinophils, basophils, or mast cells. Because the concentration of each type of leukocyte is determined by different factors, it is important to recognize that a leukocytosis is created by increased concentrations of individual cell types. The purpose of this article is to describe criteria that are used to distinguish the major disorders or conditions that produce a leukocytosis: Inflammation: depending on the type and duration of the inflammatory or immune response, inflammation may result in a neutrophilia, lymphocytosis, monocytosis, eosinophilia, mastocytemia, or, probably, basophilia. The leukocytosis involves altered production, distribution, and use of leukocytes. Glucocorticoid response: glucocorticoid hormones (eg, cortisol) or drugs (eg, prednisolone) can alter the distribution and use of leukocytes to create a neutrophilia and perhaps a monocytosis. Catecholamine response: catecholamines (ie, epinephrine, norepinephrine) can alter the distribution of leukocytes to create a neutrophilia, lymphocytosis, and possibly monocytosis or eosinophilia. The catecholamine response is associated with excitement, fright, and exercise.
Journal of the American Veterinary Medical Association, 2013
Veterinary clinical pathology / American Society for Veterinary Clinical Pathology, 2012
Reference intervals (RI) are an integral component of laboratory diagnostic testing and clinical ... more Reference intervals (RI) are an integral component of laboratory diagnostic testing and clinical decision-making and represent estimated distributions of reference values (RV) from healthy populations of comparable individuals. Because decisions to pursue diagnoses or initiate treatment are often based on values falling outside RI, the collection and analysis of RV should be approached with diligence. This report is a condensation of the ASVCP 2011 consensus guidelines for determination of de novo RI in veterinary species, which mirror the 2008 Clinical Laboratory and Standards Institute (CLSI) recommendations, but with language and examples specific to veterinary species. Newer topics include robust methods for calculating RI from small sample sizes and procedures for outlier detection adapted to data quality. Because collecting sufficient reference samples is challenging, this document also provides recommendations for determining multicenter RI and for transference and validation...
PLoS ONE, 2014
The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulator... more The cancer microenvironment plays a pivotal role in oncogenesis, containing a number of regulatory cells that attenuate the anti-neoplastic immune response. While the negative prognostic impact of regulatory T cells (Tregs) in the context of most solid tissue tumors is well established, their role in lymphoid malignancies remains unclear. T cells expressing FOXP3 and Helios were documented in the fine needle aspirates of affected lymph nodes of dogs with spontaneous multicentric B cell lymphoma (BCL), proposed to be a model for human non-Hodgkin lymphoma. Multivariable analysis revealed that the frequency of lymph node FOXP3 + T cells was an independent negative prognostic factor, impacting both progression-free survival (hazard ratio 1.10; p = 0.01) and overall survival (hazard ratio 1.61; p = 0.01) when comparing dogs showing higher than the median FOXP3 expression with those showing the median value of FOXP3 expression or less. Taken together, these data suggest the existence of a population of Tregs operational in canine multicentric BCL that resembles thymic Tregs, which we speculate are co-opted by the tumor from the periphery. We suggest that canine multicentric BCL represents a robust large animal model of human diffuse large BCL, showing clinical, cytological and immunophenotypic similarities with the disease in man, allowing comparative studies of immunoregulatory mechanisms.
Veterinary Clinical Pathology, 2008
Hyperammonemia has frequently been implicated in the pathogenesis of hepatic encephalopathy. Bloo... more Hyperammonemia has frequently been implicated in the pathogenesis of hepatic encephalopathy. Blood ammonia determination requires minimal delay between sampling and analysis for accurate results. The aim of this study was to investigate the PocketChem BA, a new point-of-care (POC) blood ammonia analyzer for clinical use by determining machine precision, linearity, repeatability, and accuracy. Coefficients of variation were determined by repeated measurement of 2 control solutions. Linearity was investigated by testing serial dilutions of a stock solution. For accuracy, samples from clinical cases were used to compare the results on the PocketChem BA with those obtained using an enzymatic reference method for canine plasma. Canine and feline patients were consecutively enrolled if blood ammonia was assayed and samples could be analyzed shortly after collection. Classification of results (as normal or high, using 100 micromol/L as a cutoff value), Bland-Altman and Deming regression plots, and intraclass correlation coefficients were used to compare the methods. Stability of samples and test strips also was assessed over time. Coefficients of variation were 10.6% and 4.8% for low and high controls, respectively. Concentrations of ammonia in diluted stock solutions correlated positively with mean measured concentrations (Pearson coefficient 0.988, P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). Of the 54 samples obtained from 38 dogs and 4 cats, 41 had ammonia concentrations within the readable range. Results from the POC analyzer and the reference method were correlated positively (intraclass coefficient 0.800, 95% confidence interval 0.655-0.888), with the POC analyzer having negative constant and proportional biases. The methods agreed in the classification of 45/54 (83.3%) samples, with 7 false negative results on the POC analyzer. Results of repeated sample and strip analyses at 1 and 24 hours were significantly different (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.05) from those at 0 hour. The PocketChem BA has acceptable precision, adequate linearity, and satisfactory agreement with a reference method, but negative constant and proportional biases. The POC analyzer may be suitable for clinical use in patients suspected of having hepatic encephalopathy, using a lower reference limit of 60 mumol/L to decrease false negative results.
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Papers by Balazs Szladovits