Prion protein genotype survey confirms low frequency of scrapie-resistant K222 allele in British goat herds.

Scrapie in goats is a transmissible, fatal prion disease, which is endemic in the British goat population. The recent success in defining caprine PRNP gene variants that provide resistance to experimental and natural classical scrapie has prompted the authors to conduct a survey of PRNP genotypes in 10 goat breeds and 52 herds to find goats with the resistant K222 allele. They report here the frequencies in 1236 tested animals of the resistance-associated K222 and several other alleles by breed and herd. Eight animals were found to be heterozygous QK222 goats (0.64 per cent genotype frequency, 95 per cent CI 0.28 to 1.27 per cent) but no homozygous KK222 goats were detected. The K222 allele was found in Saanen, Toggenburg and Anglo-Nubian goats. The fact that only a few goats with the K222 allele have been identified does not preclude the possibility to design and implement successful breeding programmes at national level.

Minimal involvement of the circumventricular organs in the pathogenesis of spontaneously arising and experimentally induced classical bovine spongiform encephalopathy.

In sheep infected experimentally with the bovine spongiform encephalopathy (BSE) agent, amplification of infectivity in peripheral organs during early preclinical stages is thought to contribute to high titres of the agent being detected in blood, with subsequent haematogenous neuroinvasion through the circumventricular organs (CVOs). In contrast, little disease-associated prion protein (PrP(d)) or infectivity is detected in the peripheral tissues of cattle during the preclinical and clinical stages of BSE. The aim of this study was to investigate immunohistochemically the role of haematogenous neuroinvasion in cattle with spontaneously arising and experimentally induced BSE. There was almost complete absence of PrP(d) in the peripheral organs of BSE infected cattle. Additionally, there was minimal involvement of the CVOs during preclinical disease and there was progressive caudorostral accumulation of PrP(d) in the brain. These findings do not support haematogenous neuroinvasion in the bovine disease.

Experimental classical bovine spongiform encephalopathy: definition and progression of neural PrP immunolabeling in relation to diagnosis and disease controls.

Tissues from sequential-kill time course studies of bovine spongiform encephalopathy (BSE) were examined to define PrP immunohistochemical labeling forms and map disease-specific labeling over the disease course after oral exposure to the BSE agent at two dose levels. Study was confined to brainstem, spinal cord, and certain peripheral nervous system ganglia-tissues implicated in pathogenesis and diagnosis or disease control strategies. Disease-specific labeling in the brainstem in 39 of 220 test animals showed the forms and patterns observed in natural disease and invariably preceded spongiform changes. A precise temporal pattern of increase in labeling was not apparent, but labeling was generally most widespread in clinical cases, and it always involved neuroanatomic locations in the medulla oblongata. In two cases, sparse labeling was confined to one or more neuroanatomic nuclei of the medulla oblongata. When involved, the spinal cord was affected at all levels, providing no indication of temporal spread within the cord axis or relative to the brainstem. Where minimal PrP labeling occurred in the thoracic spinal cord, it was consistent with initial involvement of general visceral efferent neurons. Labeling of ganglia involved only sensory ganglia and only when PrP was present in the brainstem and spinal cord. These experimental transmissions mimicked the neuropathologic findings in BSE-C field cases, independent of dose of agent or stage of disease. The model supports current diagnostic sampling approaches and control measures for the removal and destruction of nervous system tissues in slaughtered cattle.

Neuroendocrine carcinoma of the liver and gallbladder in a cow.

A 15-year-old Limousin-cross cow was presented for examination with neurological signs and serum biochemical changes consistent with liver disease. Necropsy revealed enlargement of the liver with multifocal firm, depressed, pale, circumscribed lesions throughout the parenchyma. Within the gallbladder there were exophytic and villiform mucosal masses. Microscopically, hepatic structure was displaced by neoplastic cells forming trabeculae, nests and rosettes. There was transmural infiltration of the gallbladder by similar cells. The histological pattern of growth of the neoplastic cells, the presence of silver-stained cytoplasmic granules within these cells and the immunohistochemical demonstration of chromogranin A supported the diagnosis of neuroendocrine carcinoma. Bovine liver and gallbladder neuroendocrine carcinomas are rare and this is the first detailed documentation of the disease in the United Kingdom.

Estimating the temporal relationship between PrPSc detection and incubation period in experimental bovine spongiform encephalopathy of cattle.

This study examines tissues from sequential-kill, time-course pathogenesis studies to refine estimates of the age at which disease-specific PrP (PrP(Sc)) can first be detected in the central nervous system (CNS) and related peripheral nervous system ganglia of cattle incubating bovine spongiform encephalopathy (BSE). Such estimates are important for risk assessments of the age at which these tissues should be removed from cattle at slaughter to prevent human and animal exposure to BSE infection. Tissues were examined from cattle dosed orally with 100 or 1 g BSE-infected brain. Incubation period data for the doses were obtained from attack rate and the sequential-kill studies. A statistical model, fitted by maximum likelihood, accounted for the differences in the lognormal incubation period and the logistic probability of infection between different dose groups. Initial detection of PrP(Sc) during incubation was invariably in the brainstem and the earliest was at 30 and 44 months post-exposure for the 100 g- and 1 g-dosed sequential-kill study groups, respectively. The point at which PrP(Sc) in 50 % of the animals would be detected by immunohistochemistry applied to medulla-obex was estimated at 9.6 and 1.7 months before clinical onset for the 100 g- and 1 g-dosed cattle, respectively, with a low probability of detection in any of the tissues examined at more than 12 months before clinical onset. PrP(Sc) was detected inconsistently in dorsal root ganglia, concurrent with or after detection in CNS, and not at all in certain sympathetic nervous system ganglia.

Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle.

The dose-response of cattle exposed to the bovine spongiform encephalopathy (BSE) agent is an important component of modelling exposure risks for animals and humans and thereby, the modulation of surveillance and control strategies for BSE. In two experiments calves were dosed orally with a range of amounts of a pool of brainstems from BSE-affected cattle. Infectivity in the pool was determined by end-point titration in mice. Recipient cattle were monitored for clinical disease and, from the incidence of pathologically confirmed cases and their incubation periods (IPs), the attack rate and IP distribution according to dose were estimated. The dose at which 50 % of cattle would be clinically affected was estimated at 0.20 g brain material used in the experiment, with 95 % confidence intervals of 0.04-1.00 g. The IP was highly variable across all dose groups and followed a log-normal distribution, with decreasing mean as dose increased. There was no evidence of a threshold dose at which the probability of infection became vanishingly small, with 1/15 (7 %) of animals affected at the lowest dose (1 mg).

Clinical findings in 78 suspected cases of bovine spongiform encephalopathy in Great Britain.

The clinical findings in 59 cows with bovine spongiform encephalopathy (BSE) were compared with those in 19 cattle that were submitted as BSE suspects but not confirmed by immunohistochemistry. Both groups were also compared with a control group of 20 healthy cows. Abnormalities in behaviour, temperament, mental status and activity, neurogenic disorders of gait and hyperreactivity to touch were frequently observed in the cattle with BSE. Not every animal with BSE displayed clinical signs in all these categories, and the severity of the signs was not always useful for differentiating them from the BSE suspects that were not confirmed by pathology. The neurological examination was better than passive observations for the clinical diagnosis of BSE. Tests of the animals' responses to sudden auditory, visual and tactile stimuli were very useful for distinguishing cases of BSE from unconfirmed BSE suspects if the cases did not display signs in all the categories.

Developmental memory performance: inter-task consistency and base-rate variability on the WRAML.

Two studies examined developmental memory test consistency and base-rate variability on the Wide Range Assessment of Memory and Learning (WRAML) using three age cohorts from the standardization sample. Study 1 examined inter-subtest correlation coefficients across the nine subtests of the WRAML and compared across three age cohorts (5, 11, 16 to 17 year olds). An age-related increase in inter-task consistency was found (mean r = .26 and .42 for the youngest and oldest age groups, respectively). However, correlation coefficients were generally in the low to moderate range (rs = .2 to .5) for all three cohorts suggesting considerable performance variability across memory subtests. Study 2 examined base-rate variability in the WRAML standardization sample using several different methods. More specifically, base-rate information is provided for the maximum discrepancy between subtests, profile strengths and weakness (i.e., discrepancies from the mean scaled score), and the prevalence of individuals within the "deficient" performance range (i.e., < = 2 SD below normative means). In addition, performance variability across the four WRAML index scores was examined by determining the prevalence rates for the maximum discrepancy (1) between index scores, and (2) from the General Memory Index compared to the other three index scores. Performance discrepancies tended to be higher among the youngest group. Again, however, considerable performance variability was observed across all three age cohorts. Implications for clinical practice are discussed.

Parenting alliance: a multifactor perspective.

The Parenting Alliance Measure (PAM) provides an operational representation of Weissman and Cohen's theory of parenting that has both clinical and research applications. The PAM is a 20-item, self-report instrument that measures the strength of the perceived alliance between parents of children ages 1 to 19 years. Multigroup confirmatory factor analysis was used to examine whether the PAM measures the same constructs for mothers and fathers. In addition, a formal comparison between a one- and two-factor solution was conducted, and the invariance of parameter estimates for the preferred model was tested for mothers and fathers. Results indicated that the PAM measures the same dimensions for these two groups. A formal comparison between the one- and two-factor solutions favored the less parsimonious two-factor model. At the same time, the relationship between these constructs was sufficiently high to warrant interpretation of an overall parenting alliance score. Accordingly, results from the current investigation support two levels of interpretation on the PAM. Normative raw score conversions to percentile and standardized T scores are provided.