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Case report A 5-year-old female spayed Labrador Retriever was examined for a hindlimb gait abnormality. Initial neurological examination was consistent with vestibular dysfunction. Over the course of 1 year, signs progressed to reflect cerebellar ataxia, vertical nystagmus and delayed postural reactions in all limbs. At the initial examination, subjective evaluation of magnetic resonance imaging scan of the brain was considered normal. Repeat imaging at 1 year after initial examination revealed a reduction in the size of the cerebellum. Retrospectively, the size of the cerebellum on the initial MRI was small when assessed using an objective measurement algorithm. Postmortem histopathological evaluation of the brain showed diffuse degeneration of Purkinje cell neurones with secondary granule cell loss in the cerebellum, in addition to pigment inclusions in brainstem neurones. Conclusion The clinical history and clinicopathological data are consistent with late-onset cerebellar abiotrophy, which has not previously been described in this breed.

The aim of the study was to determine the diagnostic usefulness of magnetic resonance imaging (MRI) and brainstem auditory evoked responses (BAER) in dogs suspected of having cerebellar cortical degeneration (CCD). In the years 2009–2011, six dogs with suspected CCD were examined. Both MRI and BAER examinations revealed abnormalities in all dogs (100%). By MRI, T2-weighted midsagittal images revealed an increased amount of cerebrospinal fluid (CSF) surrounding the cerebellum within the sulci of the folia in all dogs (100%). In 4 out of the 6 dogs (66.66%), cerebellar hypoplasia was more visible in the region of the dorsal cerebellar lobules. In 5 out of the 6 dogs (83.33%), the fourth ventricle was enlarged. In our studies, the brain to cerebellum ratio evaluated on the midsagittal image was 11.93%, in comparison to 14.9% in normal dogs. By BAER examination, the amplitude of the first and second waves was diminished and III–V interlatency was prolonged in 5 out of the 6 dogs (83.33%). In one out of the 6 dogs (16.67%), only the III–V interlatency was prolonged. In one dog (16.67%), somato-nervous deafness in the left ear was detected, whereas in the right ear the III–V interlatency was prolonged. MRI of the cerebellum is a reliable method for the antemortem diagnosis of CCD in American Staffordshire terriers, as is BAER examination. BAER is an objective diagnostic tool, which — along with other diagnostic modalities — can be helpful in the assessment, management and follow-up of dogs with cerebellar abiotrophy. It proved to be useful in determining the severity of neurological lesions in comparison to MRI findings, as well as in assessing the prognosis.

Background Cerebellar abiotrophy (CA) is a rare but significant disease in Arabian horses caused by progressive death of the Purkinje cells resulting in cerebellar ataxia characterized by a typical head tremor, jerky head movements and lack of menace response. The specific role of magnetic resonance imaging (MRI) to support clinical diagnosis has been discussed. However, as yet MR imaging has only been described in one equine CA case. The role of MR morphometry in this regard is currently unknown. Due to the hereditary nature of the disease, genetic testing can support the diagnosis of CA. Therefore, the objective of this study was to perform MR morphometric analysis and genetic testing in four CA-affected Arabian horses and one German Riding Pony with purebred Arabian bloodlines in the third generation. Results CA was diagnosed pathohistologically in the five affected horses (2 months - 3 years) supported by clinical signs, necropsy, and genetic testing which confirmed the TOE1:g.2171G>A SNP genotype A/A in all CA-affected horses. On MR images morphometric analysis of the relative cerebellar size and relative cerebellar cerebrospinal fluid (CSF) space were compared to control images of 15 unaffected horses. It was demonstrated that in MR morphometric analyses, CA affected horses displayed a relatively smaller cerebellum compared to the entire brain mass than control animals (P = 0.0088). The relative cerebellar CSF space was larger in affected horses (P = 0.0017). Using a cut off value of 11.0% for relative cerebellar CSF space, the parameter differentiated between CA-affected horses and controls with a sensitivity of 100% and a specificity of 93.3%. Conclusions In conclusion, morphometric MRI and genetic analysis could be helpful to support the diagnosis of CA in vivo.

The Australian Kelpie was generated from three pairs of working Scottish Collie dogs in 1870. The new breed was developed in an effort to ease the growing working demand faced by sheep farming. Like most dog breeds, inbreeding has been common within the Kelpie breed and persistent breeding of champion dogs (popular sire effect) has resulted in the spread of autosomal recessive conditions. One of these, Cerebellar Abiotrophy (CA) results in ataxia, characterized by a head tremor, poor body coordination and high stepping gait. Whole genome association and homozygosity analysis have mapped the CA locus to a 5 Mb region on chromosome 3 and identified a common SNP haplotype shared between all affecteds and some unaffected controls. This region was sequenced on a 454 platform in two affected and one control dogs. A total of 2019 differences were identified homozygous in the two affecteds compared to the control, 17 of which were synonymous substitutions in coding exons and substitutions in the untranslated regions of mRNA. On top of this, a total of 22 differences in introns and intergenic regions with high sequence conservation between other mammals and dogs were identified and investigated as possible causative mutations for CA in Kelpies. PCR and Sanger sequencing were employed to fill in 454 sequencing gaps for a total of 40 coding, non-coding exons and upstream regions of different genes within the candidate region. One intergenic (31674050) deletion conserved between other mammals and dogs was homozygous in the affecteds compared to controls and was predicted to disrupt a HSF2 transcription factor binding site for regulation of neighbouring genes. In addition, sequencing of the DMGDH gene in affected and unaffected control dogs identified a 223 bp insertion upstream of the last exon. This insertion may produce aberrant mRNA splicing and protein truncation, and may be a causative factor in the CA phenotype.

Serebellar abiotrofi birçok hayvan türünde cinsiyetten ba- ğımsız, otozomal, kalıtsal nitelikte tipik olarak Purkinje hücrelerinin progresif kaybıyla karakterize bir durumdur. Mevcut vakada travma veya başka hastalık hikayesi olmayan ataksi gözlenen bir haftalık Samoyed ırkı bulunmaktadır. Fiziksel muayenede kontrolsüz hareketler, gövdede ılımlı ataksi ve başta şiddetli titremeler gözlendi. Ayrıca köpek yerken sıkıntılı, otururken ve yürürken düşmeden sıkıntılı gözlendi. Hastada tam kan, serebrospinal sıvı analizi ve serebral radiyografi normal gözlendi. Tedavide uygulanan diazepam, vitamin B1 ile glukokortikoidler klinik belirtiler üzerine etkili olmadı ve bir ay sonra köpek öldü. Klinik ve histopatolojik belirtilere göre serebellar kortikal abiotrofi olgusu tanımlandı. Mevcut vaka Samoyed ırkı köpekte tanımlanan ilk serebellar kortikal abiotrofi özelliğinin taşımaktadır., Cerebellar abiotrophies have a non-sex-linked, autosomal, recessively inherited basis in anumber of animal species, and lesions typically reflect progressive loss of Purkinje cells. In this report, ataxia was observed in a one-week-old male Samoyed puppy with no history of trauma or any other illness. Physical examination revealed uncoordinated movements, mild trunkal ataxia and intensive head tremors, so the dog had trouble eating, evacuating and difficulties in standing and walking without falling. The complete cell count, cerebrospinal fluid analysis and cerebral radiographs were normal. Treatment with diazepam, vitamin B1 and glucocorticoids had no effect on clinical signs and the dog died after a month. According to clinical signs and histopathological features, cerebellar cortical abiotrophy was diagnosed. This is the first report of a cerebellar cortical abiotrophy in a Samoyed puppy

Cerebellar abiotrophies have a nonsex-linked, autosomal, recessively inherited basis in a number of species, and lesions typically reflect profound and progressive loss of Purkinje cells. In this report, an unusual form of abiotrophy is described for two sibling Border Collies. Extensive loss of the cerebellar granular cell layer was present with relative sparing of Purkinje cells of two female pups. The biochemical basis for this form of cerebellar abiotrophy is unknown, but the lack of disease in other siblings supports an autosomal recessive mode of inheritance.

A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid–Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P = .0104). The degeneration was significantly more pronounced dorsally than ventrally ( P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half ( P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs ( P = .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non–membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.

Equine Cerebellar Abiotrophy (CA) is a neurological disease found in Arabian horses. CA is characterized by post-natal degeneration of the Purkinje cells of the cerebellum. Signs of CA include ataxia, head tremors, and a lack of balance equilibrium. We have discovered a linkage of the CA phenotype to a microsatellite marker on ECA2 and identified a region of conserved homozygosity spanning approximately 142 kb. Complete sequencing of the four genes in this region identified one SNP found only in Arabian horses, located in exon 4 of TOE1 and approximately 1200 base pairs upstream of MUTYH, adjacent to a possible binding site for the transcription factor GATA2. qPCR analysis of cDNA from the cerebella of affected and unaffected horses suggested that MUTYH expression is down-regulated in affected horses. This SNP may therefore have a function effect on TOE1, or a regulatory effect on MUTYH by negatively affecting the binding affinity of GATA2.

A two-year-old male domestic shorthair cat was seen because of sudden onset of incoordination and tremors that had rapidly worsened over five days. Neurological examination revealed severe cerebellar ataxia, intention tremors and bilaterally decreased menace response. Blood work evaluation included a complete cell blood count (CBC), serum biochemistry profile, urinalysis, faecal flotation, cerebrospinal fluid (CSF) analysis and retroviral testing. Except for testing positive for feline immunodeficiency virus (FIV) antibodies, all other results were within the normal range. The patient was euthanased two days later because of progression of clinical signs, and a necropsy was performed. Histologically, lesions were limited to the cerebellum and consistent with cerebellar abiotrophy. No secondary diseases that could explain the rapid development of clinical signs were found. It was considered unlikely that cerebellar degeneration was related to FIV positivity, as virus invasion of the central nervous system (CNS) is mainly limited to the cerebral cortex. This case report is the first to describe late onset and rapid progression cerebellar abiotrophy in a cat.

Cerebellar abiotrophy, a premature degeneration of cerebellar neurons, has been described in most domestic animals. Affected animals typically present with progressive neurologic signs after a variable period of postnatal normalcy. This report describes the clinical, histopathologic, and immunohistochemical (IHC) findings of cerebellar abiotrophy in an alpaca. The alpaca developed intention tremors, hypermetria, and a wide-based stance at 1.5 years of age. Histologic lesions, confined to the cerebellar vermis, included marked absence of Purkinje cells, decreased granule cells, narrowing of the molecular layer, and thinning of white matter tracts consistent with abiotrophy. Increased cell processes in the molecular layer immunolabeled for glial fibrillary acidic protein, whereas immunoreactivity for neurofilament was reduced in the molecular layer and cerebellar folia white matter. To the investigators' knowledge, this is the first report of cerebellar abiotrophy in a camelid and the first documentation of IHC findings associated with this condition.

A late onset of cerebellar degeneration was diagnosed in a one-and-a-half-year-old Siamese cat. The animal had been presented with mild ataxia involving all four limbs. Over the following two years, the signs gradually progressed to severe incoordination, a frequent tendency to fall and a head tremor. The neurological signs were consistent with a diffuse cerebellar lesion and the cat was euthanased. Profound and diffuse Purkinje cell loss was found on histopathological examination, but no aetiological agent was detected.

CEREBELLAR defects are common in livestock. They can be classified into cerebellar hypoplasia, which results from arrested development of the cerebellum, and cerebellar abiotrophy, which results from accelerated or premature degeneration of formed cerebellar tissue ([Jubb and Huxtable 1985][1]).

A beagle puppy was presented with clinical signs indicative of a cerebellar disease. Histopathological evaluation of the cerebellum revealed a diffuse degenerative cortical lesion. The clinical history and the histopathological findings are consistent with a neonatal cerebellar abiotrophy. Furthermore, the breeding history supports the hypothesis of an inherited genetic disorder that is, most likely, an autosomal recessive trait.

Cerebellar abiotrophy is a degenerative condition characterized by either early or late onset of severe neurological deficits caused by the marked depletion of Purkinje cells and granule cell neurons of the cerebellar cortex. The condition has been reported in numerous species with a proposed genetic basis of transmission. Here we present the anatomopathological investigation of two closely related lion-tailed macaques. Both cases, a 9-month-old male and a 4-month-old female, shared a long history of progressively worsening ataxia, incoordination and delayed body growth. Based on the characteristic findings, diagnoses of cerebellar abiotrophy were made. The relatedness of the two cases strongly supports an inherited mode of transmission. To the authors’ knowledge, this is the first report of cerebellar abiotrophy in a macaque species.

Descrevem-se os aspectos epidemiológicos, clínicos e patológicos das enfermidades do sistema nervoso central dos ruminantes, diagnosticadas na região Sul do Rio Grande do Sul, incluindo: abiotrofia cerebelar; hipoplasia cerebelar; hipermetria hereditária; artrogripose; hipomielinogênese congênita; abscesso cerebral; listeriose; tétano; botulismo; necrose simétrica focal; raiva; leucose; encefalite por herpesvírus bovino-5; febre catarral maligna; intoxicações por Solanum fastigiatum, Claviceps paspali, Ramaria flavo-brunnescens, Halimium brasiliense e Diplodia maydis; encefalopatia hepática causada por Senecio spp. e Echium plantagineum; cetose; coenurose; e síndrome espinhal. The main epidemiological, clinical and pathologic aspects of the diseases of the nervous system in cattle in Southern Rio Grande do Sul are described, including, the following conditions: cerebellar abiotrophy; cerebellar hypoplasia; congenital hypermetria; arthrogryposis; congenital hypomyelinogenesis; brain abscess; listeriose; tetanus; botulism; focal symmetrical encephalomalacia; rabies; leucosis; encephalitis by Herpesvirus Bovine-5; bovino malignant catarrh; intoxications by Solanum fastigiatum, Claviceps paspali, Halimium brasiliense, Diplodia maydis, and Ramaria flavo-brunnescens; hepatoencephalopaty caused by Senecio spp. and Echium plantagineum; ketosis; coenurosis; and spinal syndrome.

Summary Purkinje cerebellar cells were studied in three Arabian horses aged between 6 and 8 months with clinical disorders in their movements, tremors and ataxia; the occurrence of apoptosis in this cell population was investigated by the (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labelling (TUNEL) method. Both optical and electron microscopical images showed a scant number of Purkinje cells, most of them with morphological features of apoptosis such as condensation of the nucleus and cytoplasm as well as segregation and fragmentation of the nucleus into apoptotic bodies. The TUNEL technique revealed a substantial number (65%) of positive immunoreactive Purkinje cells.

Many of the nervous and muscular locomotor disorders that affect sheep throughout Australia are commonly referred to as "staggers" syndromes. The range of clinical signs displayed by sheep suffering these disorders is sufficiently diverse to enable each syndrome to be graded into one of 5 progressive clinical groups. The first group, the limb paresis syndromes, includes the primary myopathies associated with the ingestion of Ixiolaena brevicompta, Malva parviflora, and Trachymene ochracea, as well as selenium and Vitamin E disorders, Paroo virus staggers, congenital progressive muscular dystrophy, humpy back, hypocalcaemic muscle weakness, Tribulus terrestris staggers and tetanus. The second group is characterised by limb paresis with knuckling of the fetlocks, and includes the plant-associated toxicities of Romulea rosea, Stachys arvensis, Trachyandra divaricata, and Tribulus micrococcus, together with haloxon toxicity, enzootic ataxia (copper deficiency), and the probably genetic disorders of segmental axonopathy, neuroaxonal dystrophy, and degenerative thoracic myelopathy. Other locomotor disorders that fit more loosely into this group are listerial myelitis (post-dipping staggers), vitamin A deficiency, cervico-thoracic vertebral subluxation Stypandra glauca toxicity, Ipomoea spp toxicity, ivermectin toxicity, and botulism. The third group, the falling syndromes, includes the probably genetic disorders of thalamic cerebellar neuropathy, cerebellar abiotrophy, and globoid cell leucodystrophy, together with Swainsona spp toxicity. The fourth group, the falling syndromes, includes the plant associated toxicities of phalaris staggers, perennial rye grass staggers and nervous ergotism (Claviceps paspali).(ABSTRACT TRUNCATED AT 250 WORDS)

A syndrome of cerebellar Purkinje's cell degeneration and coat color dilution was diagnosed in a family of Rhodesian Ridgeback dogs. One male and 1 female from the same litter and 1 female from a different litter were evaluated for growth retardation, inability to ambulate, and progressive ataxia. On physical examination, lateral recumbency, severe ataxia, tremors, and diluted coat color were identified. Littermates with nondiluted coat color were neurologically normal. Results of routine laboratory tests, urine metabolic screenings, and karyotype analyses were normal. Histopathologic abnormalities at necropsy included cerebellar Purkinje's cell degeneration, reduced granular cell layer thickness, and uneven distribution of macromelanosomes within hair shafts. Pedigree analysis suggested an autosomal recessive mode of inheritance. This is the first description of a genetic syndrome affecting the central nervous system and associated with coat color dilution in dogs.

During december 1992 a moose cow with severely incoordinated and atactic movements was observed at several occasions in an area 20 km north of Uppsala. She was followed by a calf with normal movements and appearance. The 31 of January the cow was found laying in the forest unable to raise and walk. She was killed by means of a rifle shot in the neck and necropsied on the spot.

A field outbreak of a previously unreported congenital nervous disorder involving the offspring of several pure-bred saddleback sows and a completely unrelated large white boar is described. The condition was successfully reproduced experimentally by assortative matings. Aetiologically it behaved as a simple autosomal recessive trait. Clinically, the condition was characterized by ataxia, dysmetria, perverse movements and serious impairment of the righting reflex. The only lesions found in the central nervous system, or elsewhere, characterized it as a functional disorder with progressive cerebellar abiotrophy.

The results show that significant increases in salivary cortisol concentration can be caused by castration and that the level of this response may differ significantly between alternative castration procedures. Control values indicate that the saliva sampling procedure is not in itself stressful. The calves used in this trial were highly trained and accustomed to being handled in the race and to the saliva sampling. We have found much higher salivary cortisol levels in spot checks on untrained calves in a yard (unpublished). The calves in this trial reacted only to the castration operation, whereas, in other situations, it is likely that calves would react also to the handling and sampling procedures. Stephens and Toner (1975) found plasma corticosteroid levels rose from 7.7 ng/ ml to 28.8 ng/ml, simply due to restraint and blood sampling. The maximum cortisol levels following surgical castration were similar to those recorded in the same calves during transportation by cattle truck (unpublished). This is in general agreement with Johnston and Buckland (1976). who found plasma cortisol levels around 10 ng/ml after castration and 20 ng/ml after transportation, using relatively infrequent blood sampling. They concluded also that the animals’ behaviour was not an accurate indicator of the actual level of stress. Some mortality and weight losses after castration of calves were found by Lofgren et al(l978). but did not occur in our study. Measurement by others of plasma total cortisol in cattle have ranged from 4.4 to 7.6 pg/lOO ml before dehorning to 14.6 f 8.7 pg/lOO ml after dehorning (Carter et al 1983), and using earlier assay methodology, Robertson et al (1958) reported plasma corticosteroid levels of 5 pg/lOO ml in “normal” cows and 7 to 18 ml in cows after rumenotomy. It is concluded that while there was undoubtedly a physiological stress response to castration in calves, its magnitude These results, although clear-cut, measure only one indicator of physiological stress. There is a need to add to this information other physiological and behavioural indicators and other husbandry considerations in the continuing task of understanding stress in animals.

Cerebellar abiotrophy affected 9 of 74 calves sired by a Poll Hereford bull over 2 successive calving seasons. The disease was characterised by episodes of recumbency and ataxia, with hypermetria and wide base stance. Clinical signs commenced between birth and 8 months of age. Two calves which were affected first at 8 months of age recovered clinically 9 months later. Histological lesions were found in the cerebellar cortex of 7 calves and consisted of segmental degeneration and loss of Purkinje cells, and axonal swellings. The clinical signs and pathological findings were consistent with bovine familial convulsions and ataxia, which has not been described previously in Australia. The clinical signs were not attributable to the lesions observed in the cerebellum and an underlying electrophysiological abnormality is proposed. The aetiology of the condition is probably genetic and appears to have a multifactorial basis.

The Charolais calf presented was found to be experiencing convulsive seizures. These seizures continued to increase in severity therefore the calf was euthanized. The significant necropsy findings were: Histological examination of the brain demonstrated degeneration of the Purkinjie cells in the cerebellum. The brain stem and spinal cord revealed a moderate degree of Wallerian degeneration. The calf’s entanglement in the electric fence could have precipitated or exaggerated the convulsive seizures. This particular selective degeneration of the Purkinjie cells of the cerebellar cortex is pathognomonic for cerebellar abiotrophy due to the characteristic pathological features, The Bovine Practitioner, No. 23 (1988 November)

Primary cerebellar cortical degeneration (CCD), also termed abiotrophy, is the spontaneous premature degeneration of fully differentiated neurological tissue. Cerebellar hypoplasia shares many morphological features with primary CCD, both conditions being characterised by decreased cerebellar size, with reduced numbers of Purkinje and granular cells. CCD has been identified in many canine breeds. This is the first report of the syndrome in a Scottish terrier. The patient presented with mild, gradually progressive ataxia. Survey radiographs of the cervical spine and cerebrospinal fluid (CSF) analysis were normal. CSF distemper and Toxoplasma titres were negative. A diagnosis of cerebellar atrophy was made based on magnetic resonance imaging. The progressive clinical signs suggested cerebellar degeneration rather than hypoplasia. On necropsy, the cerebellum showed macroscopic and microscopic changes consistent with primary CCD.

Background Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. Results Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. Conclusions This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0433-y) contains supplementary material, which is available to authorized users.