Many-body theory calculations of positronic-bonded molecular dianions.

The energetic stability of positron-dianion systems [A-; e+; A-] is studied via many-body theory, where A- includes H-, F-, Cl-, and the molecular anions (CN)- and (NCO)-. Specifically, the energy of the system as a function of ionic separation is determined by solving the Dyson equation for the positron in the field of the two anions using a positron-anion self-energy as constructed in Hofierka et al. [Nature 606, 688 (2022)] that accounts for correlations, including polarization, screening, and virtual-positronium formation. Calculations are performed for a positron interacting with H22-, F22-, and Cl22- and are found to be in good agreement with previous theory. In particular, we confirm the presence of two minima in the potential energy of the [H-; e+; H-] system with respect to ionic separation: a positronically bonded [H-; e+; H-] local minimum at ionic separations r ∼ 3.4 Å and a global minimum at smaller ionic separations r ≲ 1.6 Å that gives overall instability of the system with respect to dissociation into a H2 molecule and a positronium negative ion, Ps-. The first predictions are made for positronic bonding in dianions consisting of molecular anionic fragments, specifically for (CN)22- and (NCO)22-. In all cases, we find that the molecules formed by the creation of a positronic bond are stable relative to dissociation into A- and e+A- (positron bound to a single anion), with bond energies on the order of 1 eV and bond lengths on the order of several ångstroms.

A true congenital pancreatic cyst in a dog.

BACKGROUND: True congenital pancreatic cysts are a rare pathological process reported within feline and human literature. To date there has been no documented case of a true congenital cyst affecting a canine patient. The objective of this case report is to document the clinical findings, diagnostic investigations, surgical treatment, histopathological diagnosis and long-term outcome of a dog with a true pancreatic cyst. CASE PRESENTATION: A 5-month-old crossbreed dog was presented with a six-week history of abdominal pain, apparent bilateral pelvic limb weakness, reluctance to walk and intermittent vomiting and diarrhoea. An abdominal ultrasound examination performed by the dog's primary care veterinarian identified a large intra-abdominal structure of unclear origin. A computed tomographic examination identified a large ovoid structure measuring 156 mm in length, 95 mm in height and 89 mm in width and apparently originating from the left limb of the pancreas. An exploratory coeliotomy was performed and a partial pancreatectomy was performed to allow complete removal of the cystic structure. Histopathological analysis of sections of the wall of the large fluid-filled cyst identified a thick fibromuscular wall lined by a well regimented hyperplastic tall columnar epithelium with basally located round to ovoid nuclei featuring fine chromatin stippling and abundant apically located and surface mucin, concurrent with a true congenital pancreatic cyst. A long-term follow-up of twenty-nine months identified no clinical signs of recurrence. CONCLUSION: A partial pancreatectomy and en bloc excision of a true pancreatic cyst provided an excellent long-term outcome in a dog.

Canine NAPEPLD-associated models of human myelin disorders.

Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs. Genome-wide association study (GWAS) allowed us to map LEMP in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene, encoding an enzyme of the endocannabinoid system. We then sequenced this gene in LEMP-affected Rottweilers and identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.

Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy.

There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen-challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica.

A retrospective epidemiological analysis of risk factors for a primary necropsy diagnosis of bovine respiratory disease.

Bovine respiratory disease (BRD) is a multifactorial disease and the primary cause of both bovine morbidity and mortality in Ireland. The risk factors associated with a primary necropsy diagnosis of BRD among cattle in the traditional (non-feedlot) husbandry systems prevalent in Ireland have not been investigated previously. The aim of this case-control study was to investigate those risk factors among cattle of all ages over an 8 year period. A total of 3,090 BRD cases and 5,236 controls were matched by submitting veterinary practitioner. Univariable and multivariable analyses were performed to examine the association of selected animallevel, herd-level and environmental risk factors with case or control status using a conditional logistical regression model. Male cattle aged more than 31 days were significantly more likely to record a primary necropsy diagnosis of BRD than female cattle. Older cattle of both sexes were at increased odds of a BRD necropsy diagnosis than younger calves with the exception of female cattle aged greater than 165 days. The risk of a primary necropsy diagnosis of BRD increased with increasing herd size and decreased with increasing time in days since the last animal movement into the submitting herd. There were significantly reduced odds of a primary necropsy diagnosis of BRD in the summer (June to August) when compared with the autumn (September to November). These findings identify significant risk factors for a necropsy diagnosis of BRD under non-feedlot-type husbandry conditions.

Bovine besnoitiosis (Besnoitia besnoiti) in an Irish dairy herd.

Bovine besnoitiosis, caused by the apicomplexan protozoan parasite Besnoitia besnoiti, was diagnosed in an Irish dairy herd. This is the first diagnosis of besnoitiosis in Ireland or the UK and the most northerly European outbreak yet described. The diagnosis occurred following a farm investigation in June 2015 into an unusual dermatological problem that had been ongoing since 2010. On an annual basis, 1-2 per cent of cows in the herd exhibited clinical signs, including skin thickening, alopecia, weight loss and poor performance. Others displayed pyrexia, limb oedema, respiratory distress and reduced milk yield. Histopathological examination of skin revealed granulomatous and eosinophilic dermatitis, with characteristic intradermal protozoal cysts, consistent with cutaneous besnoitiosis. Follow-up serological testing and clinical examination of cattle (n=228) on the farm found that 68 per cent (144/212) were seropositive for B. besnoiti In addition, 51 per cent (117/228) had characteristic scleral conjunctival cysts and 68 per cent (134/198) had vulval cysts. Postmortem examination of a severely affected animal revealed typical gross and histopathological lesions of B. besnoiti infection. These results confirmed endemic infection with B. besnoiti The identification of this exotic disease highlights the importance of veterinary surveillance at both local and national level, particularly in relation to emerging diseases.

A critical role for the TLR signaling adapter Mal in alveolar macrophage-mediated protection against Bordetella pertussis.

Bordetella pertussis causes whooping cough, an infectious disease of the respiratory tract that is re-emerging despite high vaccine coverage. Here we examined the role of Toll-like receptor (TLR) adapter protein Mal in the control of B. pertussis infection in the lungs. We found that B. pertussis bacterial load in the lungs of Mal-defective (Mal(-/-)) mice exceeded that of wild-type (WT) mice by up to 100-fold and bacteria disseminated to the liver in Mal(-/-) mice and 50% of these mice died from the infection. Macrophages from Mal(-/-) mice were defective in an early burst of pro-inflammatory cytokine production and in their ability to kill or constrain intracellular growth of B. pertussis. Importantly, the B. pertussis bacterial load in the lungs inversely correlated with the number of alveolar macrophages. Despite the maintenance and expansion of other cell populations, alveolar macrophages were completely depleted from the lungs of infected Mal(-/-) mice, but not from infected WT mice. Our findings define for the first time a role for a microbial pattern-recognition pathway in the survival of alveolar macrophages and uncover a mechanism of macrophage-mediated immunity to B. pertussis in which Mal controls intracellular survival and dissemination of bacteria from the lungs.

Innate resistance to tuberculosis in man, cattle and laboratory animal models: nipping disease in the bud?

Tuberculosis (TB) does not always develop in people or cattle exposed to the disease and some exposed individuals may not exhibit evidence of infection. Such variability in susceptibility may be mediated through host innate immunity, non-specific inflammatory responses that may successfully eliminate infection or at least reduce the infectious load, thus modulating and easing the burden on the subsequent acquired immune response. Assessing evidence from research in man, cattle and laboratory animal models, this review appraises the role of innate immunity in TB including the role of particular leucocytes (i.e. macrophages, neutrophils, γδ-T lymphocytes and natural killer cells), endogenous host defence compounds (i.e. cathelicidin, human neutrophil peptide, lipocalin and natural resistance-associated membrane protein-1) and, in particular, vitamin D. Innate responses may be particularly important in neonatal animals and people where adaptive responses have not yet established and their success in preventing the establishment of infection may be predicated on dose and/or route of infection as well as on characteristics of the infecting isolate. Innate defences could potentially be exploited in novel vaccination and immunotherapeutic approaches to disease control, modulating their effectiveness through the use of defined mycobacterial peptides as adjuvants or therapeutics. Such novel immunomodulatory compounds may be particularly relevant in countering emerging multi- and extremely drug-resistant strains of Mycobacterium tuberculosis (Mtb).

Transgenerational effects of feeding genetically modified maize to nulliparous sows and offspring on offspring growth and health.

This study assessed the effect of feeding genetically modified maize expressing a truncated form of the Cry1Ab protein from Bacillus thuringiensis (Bt MON810 maize) to sows during gestation and lactation and their offspring from weaning to 115 d postweaning on offspring growth and health. After weaning at approximately 28 d of age (d 0), individually penned, mixed sex pigs (approximately 8 kg BW) from sows fed isogenic or Bt maize diets were blocked by sow treatment, sex, and BW and randomly assigned to Bt or isogenic maize diets as follows: i) isogenic maize-fed sow/isogenic maize-fed offspring (iso/iso); ii) isogenic maize-fed sow/Bt maize-fed offspring (iso/Bt); iii) Bt maize-fed sow/isogenic maize-fed offspring (Bt/iso); and iv) Bt maize-fed sow/Bt maize-fed offspring (Bt/Bt). Growth performance was recorded at intervals to harvest at approximately 105 kg BW (n=15/treatment) and blood samples were taken for biochemical analysis on d 0, 30, 70, 100, and 115 postweaning (n=10/treatment). Pigs were harvested on d 115 postweaning (n=10/treatment), and carcass weight, backfat depth, and organ weights (heart, kidney, spleen, and liver) were recorded. Kidney, liver, lymph nodes, and small intestine were collected for histological analysis. Offspring from Bt maize-fed sows were heavier than offspring from isogenic maize-fed sows on d 30 (P<0.05), 100 (P<0.05), and 115 postweaning (P<0.05) and had greater overall ADG (P<0.05). Overall ADFI was greater for offspring from sows fed Bt maize (P<0.05) and for Bt maize-fed pigs (P<0.05). Offspring from Bt maize-fed sows had greater carcass (P<0.05) and lighter spleen (P<0.05) weights. Dressing percentage was greater for Bt maize-fed pigs than isogenic maize-fed pigs (P<0.05), and livers were lighter for pigs in the Bt/Bt group than pigs in the iso/Bt or Bt/iso group (P<0.05). Offspring from Bt maize-fed sows also had greater duodenal crypt depths (P<0.05) and lower villus height/crypt depth ratios (P<0.05). No pathology was observed in the organs, and serum biochemistry values generally remained within normal limits and no overall differences were observed, with the exception of overall γ glutamyltransferase, which was less for pigs on the Bt/Bt treatment than pigs on the iso/Bt and Bt/iso treatments. These results indicate that transgenerational consumption of Bt maize diets is not detrimental to pig growth and health.

Effect of feeding genetically modified Bt MON810 maize to ∼40-day-old pigs for 110 days on growth and health indicators.

A total of 72 male weaned pigs were used in a 110-day study to investigate the effect of feeding genetically modified (GM) Bt MON810 maize on selected growth and health indicators. It was hypothesised that in pigs fed Bt maize, growth and health are not impacted compared with pigs fed isogenic maize-based diets. Following a 12-day basal period, pigs (10.7 ± 1.9 kg body weight (BW); ∼40 days old) were blocked by weight and ancestry and randomly assigned to treatments: (1) non-GM maize diet for 110 days (non-GM), (2) GM maize diet for 110 days (GM), (3) non-GM maize diet for 30 days followed by GM maize diet up to day 110 (non-GM/GM) and (4) GM maize diet for 30 days followed by non-GM maize diet up to day 110 (GM/non-GM). BW and daily feed intake were recorded on days 0, 30, 60 and 110 (n = 15). Body composition was determined by dual energy X-ray absorptiometry (n = 10) on day 80. Following slaughter on day 110, organs and intestines were weighed and sampled for histological analysis and urine was collected for biochemical analysis (n = 10). Serum biochemistry analysis was performed on days 0, 30, 60, 100 and 110. Growth performance and serum biochemistry were analysed as repeated measures with time and treatment as main factors. The slice option of SAS was used to determine treatment differences at individual time points. There was no effect of feeding GM maize on overall growth, body composition, organ and intestinal weight and histology or serum biochemistry on days 60 and 100 and on urine biochemistry on day 110. A treatment × time interaction was observed for serum urea (SU; P < 0.05), creatinine (SC; P < 0.05) and aspartate aminotransferase (AST; P < 0.05). On day 30, SU was lower for the non-GM/GM treatment compared with the non-GM, GM and GM/non-GM treatments (P < 0.05). On day 110, SC was higher for the non-GM/GM and GM/non-GM treatments compared with non-GM and GM treatments (P < 0.05). Overall, serum total protein was lower for the GM/non-GM treatment compared with the non-GM/GM treatment (P < 0.05). The magnitude of change observed in some serum biochemical parameters did not indicate organ dysfunction and the changes were not accompanied by histological lesions. Long-term feeding of GM maize to pigs did not adversely affect growth or the selected health indicators investigated.

A new C-Peptide correction model used to assess bioavailability of regular human insulin.

The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.

Genetic influence on the kinetics and associated pathology of the early stage (intestinal-hepatic) migration of Ascaris suum in mice.

The generative mechanism(s) of aggregation and predisposition to Ascaris lumbricoides and A. suum infections in their host population are currently unknown and difficult to elucidate in humans and pigs for ethical/logistical reasons. A recently developed, optimized murine model based on 2 inbred strains, putatively susceptible (C57BL/6j) and resistant (CBA/Ca) to infection, was exploited to elucidate further the basis of the contrasting parasite burdens, most evident at the pulmonary stage. We explored the kinetics of early infection, focusing on the composite lobes of the liver and lung, over the first 8 days in an effort to achieve a more detailed understanding of the larval dispersal over time and the point at which worm burdens diverge. Larval recoveries showed a heterogenous distribution among the lobes of the lungs, being higher in the right lung of both strains, and in the susceptible strain larvae accumulating preferentially in 2 (caudal and middle) of the 4 lobes. Total larval burdens in these 2 lobes were largely responsible for the higher worm burdens in the susceptible strain. While total lung larval recoveries significantly differed between mouse strains, a difference in liver larval burdens was not observed. However, an earlier intense inflammatory response coupled with more rapid tissue repair in the hepatic lobes was observed in CBA/Ca mice, in contrast to C57BL/6j mice, and it is possible that these processes are responsible for restricting onward pulmonary larval migration in the resistant genotype.

The experimental induction of leukoencephalomyelopathy in cats.

Leukoencephalomyelopathy of undetermined etiology has been described in specific pathogen-free cats. A study was established to assess if the long-term feeding of a gamma-irradiated diet could induce this disease. Cats fed exclusively on diet irradiated at 25.7-38.1 kGy ("typical" dose) and 38.1-53.6 kGy (high-end dose), respectively, developed typical lesions with attendant, progressively severe ataxia between study days 140 and 174. The onset of ataxia at day 140 and the number of animals affected at this time were similar in animals fed each ration. A maximum ataxia "score" was first reached by an animal on the high-end dose diet on day 167 and by 2 cats fed the "typical-end" dose diet 21 days later. Ataxic cats and 1 animal euthanized on day 93 prior to the onset of ataxia exhibited varying degrees of Wallerian degeneration in the spinal cord and brain, similar to the spontaneous disease. The elevated total antioxidant status of spinal cord segments and hepatic superoxide dismutase concentration of cats fed typical and high-end treated diets suggested free-radical involvement in the pathogenesis. The significantly elevated peroxide concentrations of the irradiated diets (1,040% and 6,440% of untreated values) may have resulted in increased oxidative insult, a factor possibly exacerbated by the treated diets' reduced vitamin A content. This study has reproduced leukoencephalomyelopathy in cats similar to spontaneous outbreaks by feeding a gamma-irradiated dry diet with elevated peroxide and reduced vitamin A concentrations.

Co-Infection of cattle with Fasciola hepatica and Mycobacterium bovis- immunological consequences.

Fasciola hepatica, the liver fluke, is a common parasite of cattle in much of the world. Previously, we have shown that cattle infected with F. hepatica have altered responsiveness (delayed type hypersensitivity reaction and cytokine responses) to M. bovis BCG infection. We hypothesized that co-infection with F. hepatica would, likewise, alter the immune response of cattle to virulent M. bovis infection, with possible implications for disease diagnosis and disease progression. Our previous work with F. hepatica/M. bovis BCG-infected cattle demonstrated a reduction in interferon (IFN)-gamma responsiveness in co-infected animals. Similar findings are reported here with virulent M. bovis following aerosol infection. The epidemiological significance of these findings, also, require exploration, particularly in view of the considerable resources devoted to the diagnosis and eradication of bovine tuberculosis, and the high prevalence of F. hepatica infection in areas where eradication has proved difficult.

Leukoencephalomyelopathy in specific pathogen-free cats.

Investigations were carried out on 8 specific pathogen-free cats (5 male and 3 female) from a colony experiencing "outbreaks" of progressive hind limb ataxia in 190 of 540 at-risk animals ranging from 3 months to 3 years old. These studies identified moderate to severe bilateral axonal degeneration within white matter regions of the cervical, thoracic, and lumbar spinal cord and in the white matter of the cerebral internal capsule and peduncle, in the roof of the fourth ventricle and inferior cerebellar peduncle, and in the external arcuate and pyramidal fibres of the medulla. There were varying degrees of accompanying microgliosis, astrocytosis, and capillary hyperplasia. Such a clinicopathologic syndrome, termed feline leukoencephalomyelopathy, has previously been described in cat colonies in Britain and New Zealand, although its etiology has not been determined. The degenerative nature of the lesions and their bilateral distribution suggest possible nutritional, metabolic, or toxic causes. Although these findings provide circumstantial evidence that the exclusive feeding of a gamma-irradiated diet of reduced vitamin A content is associated with the development of the neuronal lesions, further tissue micronutrient and antioxidant analysis will be required to support this hypothesis.

The migration of Ascaris suum larvae, and the associated pulmonary inflammatory response in susceptible C57BL/6j and resistant CBA/Ca mice.

Ascariasis is an important infection in humans (Ascaris lumbricoides) and pigs (Ascaris suum) and individuals appear to be predisposed to either heavy or light worm burdens. These extremes of susceptibility and resistance are represented in a mouse model by 2 strains of mice, CBA mice showing high resistance to infection and C57BL/6 which are highly susceptible, as reflected in worm burdens in the lungs 6-7 days after infection. In an attempt to identify the point at which the difference between these 2 strains is first manifested, we quantified worm burdens at key stages during infection leading up to the pulmonary stage of development. Thus mice were inoculated with fully embryonated A. suum eggs and larval burdens were enumerated in the large intestine and rectum, liver and lungs of the 2 strains at 6 h post-inoculation (p.i.) and on each of days 1-8 p.i. inclusively. A higher percentage of the total inoculum was recovered from the intestine/rectum of C57BL/6j mice in contrast to CBA/Ca mice at 6 h p.i. Larvae were recovered from the intestinal contents and also whilst actively migrating through the large intestinal wall. The number of larvae recovered was significantly reduced in CBA/Ca mice in contrast to C57BL/6j mice between the phase of migration from the liver and arrival in the lungs. The combined results of the inoculation of mice with corticosteroids and the examination of the change in profile and number of leukocytes present in bronchoalveolar lavage fluid suggested that the pulmonary inflammatory immune response was not prominently involved in primary protection of mice to A. suum infection in the latter days of infection in the lungs. The susceptible C57BL/6j mice produced a BAL response almost twice as intense as that of resistant CBA/Ca mice with stronger neutrophil, lymphocyte and eosinophil but not macrophage components, suggesting that the difference in worm burdens between the strains was generated earlier in the course of infection. These results were further corroborated by a histological examination of the lung tissues which showed that the passage of the larval stages of A. suum through the mouse lungs was associated with a marked inflammatory response in both strains. Again, C57BL/6j mice exhibited increased inflammation relative to CBA/Ca mice. Hence some hepatic/post-hepatic factor that varies between the 2 strains, but exerts its effect before the lung phase plays a critical role in determining the success of larvae through the host tissues. The possible sites of this host defence are reviewed.

gammadelta T cells regulate the early inflammatory response to bordetella pertussis infection in the murine respiratory tract.

The role of gammadelta T cells in the regulation of pulmonary inflammation following Bordetella pertussis infection was investigated. Using a well-characterized murine aerosol challenge model, inflammatory events in mice with targeted disruption of the T-cell receptor delta-chain gene (gammadelta TCR-/- mice) were compared with those in wild-type animals. Early following challenge with B. pertussis, gammadelta TCR-/- mice exhibited greater pulmonary inflammation, as measured by intra-alveolar albumin leakage and lesion histomorphometry, yet had lower contemporaneous bacterial lung loads. The larger numbers of neutrophils and macrophages and the greater concentration of the neutrophil marker myeloperoxidase in bronchoalveolar lavage fluid from gammadelta TCR-/- mice at this time suggested that differences in lung injury were mediated through increased leukocyte trafficking into infected alveoli. Furthermore, flow cytometric analysis found the pattern of recruitment of natural killer (NK) and NK receptor+ T cells into airspaces differed between the two mouse types over the same time period. Taken together, these findings suggest a regulatory influence for gammadelta T cells over the early pulmonary inflammatory response to bacterial infection. The absence of gammadelta T cells also influenced the subsequent adaptive immune response to specific bacterial components, as evidenced by a shift from a Th1 to a Th2 type response against the B. pertussis virulence factor filamentous hemagglutinin in gammadelta TCR-/- mice. The findings are relevant to the study of conditions such as neonatal B. pertussis infection and acute respiratory distress syndrome where gammadelta T cell dysfunction has been implicated in the inflammatory process.

The pathogenesis and pathology of bovine tuberculosis with insights from studies of tuberculosis in humans and laboratory animal models.

This paper reviews key insights the discipline of pathology has contributed to our understanding of bovine tuberculosis in the context of findings of studies of tuberculosis in humans and laboratory animal models. Analysis and extrapolation of data from other species have the potential to expand our understanding of the pathogenesis of the disease in cattle. The distribution of lesions in affected cattle, humans and laboratory animals illustrate the primacy of the respiratory tract as portal of infection and raise questions about the role of the upper respiratory tract surface, tonsil and dorsal lung regions in disease pathogenesis and transmission. The mechanisms behind significant pathological processes such as necrosis, apoptosis and liquefaction, occurring within lesions, are explored and their potential practical significance assessed in the context of herd disease dynamics and vaccine development. It is proposed that effective 'innate' host defences result in many animals and humans remaining disease-free and tuberculin test negative following exposure to infection. Furthermore, the concepts of latency and disease reactivation, considered significant factors in perpetuating tuberculosis in human populations, are explored in the context of the bovine disease.