[HPV-associated carcinomas of the female genital tract. Molecular mechanisms of development]. / HPV-assoziiertes Karzinom des weiblichen Genitaltrakts. Molekulare Mechanismen der Entstehung.

Infections with human papillomaviruses (HPV) are a common occurrence in both men and women. In contrast HPV-associated neoplasias are relatively rare and occur only in certain areas of the body. The virus has obviously developed efficient mechanisms for its persistence without inducing too much damage to the host. The formation of neoplasia seems to be more an exception. Epigenetic mechanisms play an important role in the regulation of viral gene expression. Investigations have indicated that exactly the transition from the permissive infection stage to a transformation stage, where neoplastic alterations can occur due to expression of the viral oncogenes, is associated with certain methylation patterns of the viral genome which promote the expression of the oncogenes E6 and E7. The transforming stage is seen as the actual carcinogenic event and can be immunohistochemically detected by the biomarker p16(INK4a).

Infection-specific particle from the unconventional slow virus diseases.

Scrapie-associated fibrils, first observed in brains of scrapie-infected mice, were also observed in scrapie-infected hamsters and monkeys, in humans with Creutzfeldt-Jakob disease, and in kuru-infected monkeys. These fibrils were not found in a comprehensive series of control brains from humans and animals affected with central nervous system disorders resulting in histopathologies, ultrastructural features, or disease symptoms similar to those of scrapie, kuru, and Creutzfeldt-Jakob disease. These fibrils are also found in preclinical scrapie and in the spleens of scrapie-infected mice; they are a specific marker for the "unconventional" slow virus diseases, and may be the etiological agent.

Intracerebral inoculation of experimental animals with brain tissue from patients with schizophrenia. Failure to observe consistent or specific behavioral and neuropathological effects.

To test the possibility that some cases of schizophrenia result from infection with a transmissible slow viral agent, 57 experimental animals (six chimpanzees, 12 Old World monkeys, 17 New World monkeys, and 22 guinea pigs) were inoculated intracerebrally with brain tissue from ten patients and followed up for six years. Behavioral comparisons with control animals revealed no consistent behavioral differences. Histological, immunohistochemical, and morphometric examination of brains of animals that died revealed no specific neuropathological abnormalities. These findings do not support a role for a virus-induced slow infection in the pathogenesis of schizophrenia but must be weighed against methodological limitations in animal susceptibility, disease communicability, and assay sensitivity.

Antiserum to scrapie-associated fibril protein reacts with amyloid plaques in familial transmissible dementia.

Scrapie-associated fibrils (SAF) are disease-specific markers for the unconventional agent-induced, transmissible spongiform encephalopathies. Polyclonal rabbit antiserum to SAF protein was reacted with brain sections from scrapie-infected mice, two familial cases of transmissible dementia, and three cases of Alzheimer's disease (AD). Specific immunostaining of cerebral amyloid plaques occurred in the scrapie-infected mice and in the two familial cases of transmissible dementia. No immunoreactivity was detected in senile plaques or neurofibrillary tangles in the three cases of AD. Our results suggest that SAF, the causative pathogenic agent, and extracellular deposits of amyloid in the brain are closely related. Immunohistochemical detection of SAF protein could serve as a useful diagnostic adjunct in the postmortem evaluation of difficult cases of dementia. The identification of SAF protein in the brains of two affected members of a family combining the clinical and pathological features of Creutzfeldt-Jakob disease (CJD) and the Gerstmann-Straüssler syndrome (GSS) substantiates earlier conclusions of a nosological relationship between the two. Our study provides further evidence of the similarity of SAF protein to prion protein (PrP 27-30).

Clinical significance of types of cerebellar amyloid plaques in human spongiform encephalopathies.

We report three patients with both spongiform encephalopathy and cerebellar amyloid plaques; one showed kuru-like plaques and was diagnosed as having Creutzfeldt-Jakob disease (CJD), and two had multicentric plaques and were diagnosed as having Gerstmann-Sträussler-Scheinker disease (GSSD). Evaluation of these cases and review of others previously reported suggests a clinicopathologic correlation between type of cerebellar plaque and neurologic clinical course. CJD patients who showed kuru-like plaques generally had disease with early onset (average age, 49.1 years) and long duration (average, 34 months), as compared with CJD patients without kuru-like plaques. GSSD patients usually had multicentric cerebellar plaques, and cases were usually familial, had early age of onset (average, 42.7 years), and were of long duration (average, 73 months). Myoclonus was infrequent in GSSD patients and pathologically spongiform change was minimal; spinal tract degeneration was common.

Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family.

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimer's disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Lentivirus-induced arthritis. Chronic disease caused by a covert pathogen.

Lentiviruses are exogenous, nononcogenic retroviruses that cause persistent infections in monocytes and macrophages. Among the clinical manifestations of such infections in sheep and goats is a slowly progressive arthritis, primarily involving the carpal joints of adult animals. Initially, clinical disease begins as synovitis; this progresses to involve surrounding connective tissues and osseous structures as inflammation increases and progresses. Inflammatory cells include macrophages, lymphocytes, and plasma cells. Macrophages and monocytes are the only cells that are infected with virus and in the inflamed joint may represent 50 per cent of the cells in the synovial fluid. However, only a small number of these cells are infected. Cytotoxic T lymphocytes predominate over helper T lymphocytes in the synovial fluid. The role of these cells in the pathogenesis of disease is not currently known. The pathogenesis of disease caused by these lentiviruses is related to the infection of the monocyte-macrophage cells in the animal. This event, along with virus-specific factors, render the host incapable of eliminating the virus. Despite persistence of the virus, viral replication is maintained at a tightly restricted level at all times in the infected animal. This is achieved by factors that regulate the maturation of monocytes. Basically, the infection is latent in monocytes and its precursors and becomes more productive as the cells mature. The maturing infected macrophage presents a portion of the viral proteins that it synthesizes on its cell surface in close association with class II major histocompatibility complex antigens. Lymphocytes react with this cell and produce interferon. This lymphokine induces further expression of Ia antigens. This feedback loop of Ia expression, together with persistence of the virus, maintains macrophages in a constant state of antigen presentation. This forms the trigger for the inflammatory condition that eventually leads to the degenerative lesions seen in the joint.

Sporadic ALS/MND: a global neurodegeneration with retroviral involvement?

Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out.

Pathology of dendrites in subacute spongiform virus encephalopathies.

The spongiform changes in the cerebral cortex of scrapie mice and of chimpanzees afflicted with experimental kuru and Creutzfeldt-Jakob disease were examined by electron microscopy. The pathognomonic findings consisted of swelling and vacuolation of neurons, particularly of dendrites. Fusion of swollen cells and processes occurred. The changes were associated with alterations of plasma membranes. Curled fragments of membranes accumulated at points of cell fusion and at the margin of vacuoles within dendrites. The abnormal membranes were wider and more osmiophilic than normal plasma membranes. These findings as well as other data on the nature of the atypical viruses of scrapies, kuru, and Creutzfeldt-Jakob disease indicate that the infectious agents are closely associated with membranes and that alterations of neuronal membranes initiate the spongiform degeneration of neurons.

Bovine spongiform encephalopathy: detection and quantitation of fibrils, fibril protein (PrP) and vacuolation in brain.

Bovine spongiform encephalopathy (BSE) is a new disease of cattle which has considerable homology with scrapie, the archetype of the transmissible spongiform encephalopathies. Abnormal brain fibrils, called scrapie associated fibrils (SAF), are specific ultrastructural markers for these diseases. Fibril detection was compared with histopathological diagnosis in the brains of 167 cattle; 157 clinically suspect BSE and 10 clinically normal. Fibrils were detected in samples of pooled brain regions of 67/144 in which vacuolar changes of BSE were confirmed, but absent in the remaining 23 brains, in which no vacuolation was found, including those from the clinically normal cattle and 13 with alternative neuropathological diagnoses. When eight defined anatomic regions from the brains of another 22 affected cows were examined, the sensitivity of fibril detection was greater than 90% for the brain stem areas. Fibril prevalence in these areas approximated to severity of vacuolar changes. When the same defined regions from four of the affected cows were assayed for fibril protein (PrP) by western blotting, the density of immuno-labelling generally correlated with the fibril prevalence. This study confirms the specificity of fibril detection for BSE, shows that the ease of fibril detection depends on anatomic region sampled and suggests an association between PrP accumulation and vacuolar changes in certain neuroanatomic areas.

"Limbic predilection in Alzheimer dementia: is reactivated herpesvirus involved?".

In the brains of patients with senile dementia of the Alzheimer type (SDAT), the quantitatively pathognomonic neuronal lesions (tangles, plaques, granulovacuolar degeneration, Hirano bodies, and nerve cell loss) are predisposed to occur especially within the limbic system. Anatomical and physiological studies indicate that fibres from the trigeminal ganglia innervate meninges and vessels within the middle and anterior cranial fossae, especially in the same subfrontal and mesial temporal regions preferentially afflicted in acute herpes encephalitis. These limbic regions are critical for normal memory processing and recall. Explantation and cocultivation techniques have recently demonstrated Herpes simplex virus in many humans trigeminal ganglia, which also reveal a life-long lymphocytic infiltration in the absence of any pathological changes in the sensory neurones. These lymphocytes may represent a histological marker of latent herpes virus, which when reactivating is well-established as the ganglionic source of recurrent herpes labialis. It is suggested that reactivation of the same dormant viral material travelling centripetally instead might be the cause of the "degenerative" lesions typical both of Alzheimer's Disease and of the normal aged human brain.

Pathogenesis of subacute spongiform encephalopathies.

The subacute spongiform encephalopathies include scrapie of sheep, transmissible mink encephalopathy, and kuru and Creutzfeldt-Jakob disease of man. These diseases are caused by filterable infectious agents with unique physical properties. The usual sources of infection in nature are not completely known. Epidemiological evidence suggests that the agents may enter the body through breaks in the skin and mucous membranes. Experimental studies of scrapie after subcutaneous inoculation demonstrated early replication of the agent in lymphoid tissues and later appearance in other organs; as the amount of agent in the central nervous system (CNS) increased, it decreased in or disappeared from lymphoid tissues. In preliminary studies of kuru and Creutzfeldt-Jakob disease, the infectious agents were regularly recovered from the brains of clinically-ill patients and experimental animals but only occasionally from organs outside the CNS. It remains to be seen if early events in the pathogenesis of the two human diseases, before the appearance of clinical signs, are similar to those in scrapie.

Spongiform encephalopathies in Cervidae.

The known host range of naturally-occurring transmissible spongiform encephalopathies has expanded in recent years to include wild ruminants. Chronic wasting disease (CWD) occurs in mule deer (Odocoileus hemionus hemionus) and Rocky Mountain elk (Cervus elaphus nelsoni) in Colorado and Wyoming, United States of America. These species belong to the family Cervidae. Cases have occurred primarily in captive animals but a few affected free-ranging animals have been identified. Clinical disease in both species is characterised by progressive weight loss, behavioural alterations and excessive salivation. In deer polydipsia and polyuria also commonly occur. Significant lesions are confined to the central nervous system and consist of spongiform change in grey matter, intraneuronal vacuolation, astrocytosis and amyloid plaques. Inflammatory reaction is absent. The origin of this disease is not known. In contrast to the cases of spongiform encephalopathy recognised in five species of antelope (family Bovidae) in British zoological parks, which are an extension of the current bovine spongiform encephalopathy epizootic, CWD is not the result of food-borne exposure to the infectious agent. CWD appears to be maintained within captive populations by lateral and, possibly, maternal transmission. Spongiform encephalopathies in wild ruminants are currently geographically isolated and involve relatively small numbers of animals. However, these potentially transmissible diseases could be of greater importance in the future and should be viewed with concern in the light of international movements of wild ruminants and the current expansion of the game farming and ranching industry in many parts of the world.

Experimental infection of sheep by caprine arthritis-encephalitis virus and goats by progressive pneumonia virus.

The lentiviruses, caprine arthritis-encephalitis virus (CAEV) and progressive pneumonia virus (PPV) of sheep, cause major diseases in their respective hosts; however, the infectivity of these viruses for closely related species has not been determined. Experiments were conducted to determine whether CAEV would infect sheep and whether PPV would infect goats. Upon inoculation with CAEV, lambs developed a nonsuppurative arthritis and antibody to CAEV, and the virus was isolated up to 4 months later. Exposure of 3 lambs to CAEV-infected adult goats did not lead to demonstrable infection after 18 months. Young goats inoculated with PPV replicated the virus and developed arthritis and antiviral antibody. These results demonstrate that these distinctly different lentiviruses may infect and cause diseases in species other than their accustomed host. Presently used techniques may not be effective in differentiating which lentivirus is responsible for infection of sheep and goats. Our results also indicate that mixing sheep and goats may adversely influence attempts to eradicate lentiviruses from these species.

Spongiform encephalopathy of Rocky Mountain elk.

A disease with striking clinical and pathologic similarities to the spongiform encephalopathies is described in six Rocky Mountain elk (Cervus elaphus nelsoni) maintained in wildlife facilities in Colorado and Wyoming. Clinical signs included behavioral alterations and progressive weight loss over a period of weeks or months. Consistent microscopic lesions were limited to the central nervous system and characterized by widespread spongiform transformation of the neuropil, intracytoplasmic vacuoles in neuronal perikaryons, and astrocytic hypertrophy and hyperplasia.

A chronic indurative mastitis in sheep, associated with maedi/visna virus infection.

A possible association of a chronic indurative mastitis with mvv (maedi visna virus) infection in sheep was investigated. Sheep of four flocks (group A), in which insufficient lamb growth apparently associated with insufficient milk production and probably related to udder induration, was a serious problem, were clinically examined in mid-lactation. The results were compared with four mvv-free flocks (group B) without such complaints. The incidence of udder induration in group A (n = 263) was about eight times higher than in group B (n = 206): 63.1 versus 8.0%. The clinical picture differed essentially between the groups. In group A the udder abnormalities were of a diffuse and indurative nature, involving both udder halves, while in group B the udder lesions were mainly nodular and often limited to one udder half. Bacteriological examination revealed a difference in infection rate of the udders (6.8% in group A versus 14.1% in group B). A substantial difference was observed in a comparison of the bacteriological infection rate of the clinically abnormal udders (5.4% in group A, versus 47.0% in group B). Serological examination with an indirect ELISA revealed 81% seropositive sheep in group A, versus 0% in group B. Twelve sheep of group A and five of group B, called for reason of mastitis, were selected for pathological examination. The gross and microscopic lesions showed a pronounced difference between both groups. In group A a diffuse interstitial mastitis with slight to moderate fibrosis and a pronounced lymphoid hyperplasia was observed. In group B the mastitis had a nodular character, with a chronic galactophoritis, extensive fibrosis, and in some cases chronic abscesses.(ABSTRACT TRUNCATED AT 250 WORDS)

Spongiform encephalopathy in an arabian oryx (Oryx leucoryx) and a greater kudu (Tragelaphus strepsiceros)

Clinical, pathological and epidemiological details of scrapie-like encephalopathies are described in an arabian oryx and a greater kudu. Clinical signs included ataxia and loss of condition with a short, progressive clinical course (22 and three days, respectively). Histopathological examination of the brains revealed spongiform encephalopathy characteristic of that observed in scrapie and bovine spongiform encephalopathy (BSE). It seems probable that these cases have a common aetiology with BSE. Scrapie-like spongiform encephalopathies have now been described in five species of exotic artiodactyls in Britain indicating a, hitherto inapparent, wider range of ruminant species as natural hosts for these diseases.

A spongiform encephalopathy in a cat.

A cat which developed a change of temperament, with muscle tremors, ataxia and pupillary dilatation was suspected and later confirmed histopathologically to have a spongiform encephalopathy. The case is of special interest in view of the widespread concern about spongiform encephalopathies as a result of the recent epidemic of bovine spongiform encephalopathy.

Scrapie-like encephalopathy in a greater kudu (Tragelaphus strepsiceros) which had not been fed ruminant-derived protein.

A 19-month-old greater kudu (Tragelaphus strepsiceros), whose dam had died 15 months earlier with spongiform encephalopathy, required euthanasia after developing severe ataxia and depression with an apparently sudden onset. No macroscopic abnormalities were detected on post mortem examination but a scrapie-like spongiform encephalomyelopathy was apparent on histopathological examination of brain and segments of spinal cord. Negative stain electron microscopy of proteinase K-treated detergent extracts of tissue from the brain stem revealed the presence of scrapie associated fibrils, and a 25 to 28 kDa band comparable with that identified as abnormal PrP (prion protein) from the brains of domestic cattle with spongiform encephalopathy was detected using rabbit antiserum raised against mouse PrP. The animal was born nine months after the statutory ban on the inclusion of ruminant-derived protein in ruminant feeds and, as no other possible sources of the disease were apparent, it appears likely that the infection was acquired from the dam.

Naturally occurring scrapie-like spongiform encephalopathy in five domestic cats.

Naturally occurring transmissible spongiform encephalopathies have been recognised in sheep, man, mink, captive deer and cattle. Recently a similar disease was reported in a domestic cat. This paper describes the clinical and pathological findings in five cats with similar signs, including further observations on the original case. All the cats had a progressive, neurological disease involving locomotor disturbances, abnormal behaviour and, in most cases, altered sensory responses. Histopathological examination of the central nervous system revealed changes pathognomonic of the scrapie-like encephalopathies, including widespread vacuolation of the grey matter neuropil, vacuolation of neuronal perikarya and an astrocytic reaction.