[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).

Prion diseases.

There have been remarkably rapid advances in the understanding of prion diseases over the past year. The controversial notion that the transmissible agent may be an abnormal isoform of a host-encoded protein, the prion protein, is now gaining wide acceptance. The conundrum of how a disease can both be inherited as an autosomal dominant condition and also be experimentally transmissible by inoculation is beginning to make sense.

Gerstmann-Sträussler-Scheinker disease. I. Extending the clinical spectrum.

We present the clinical findings in affected members of a large kindred with Gerstmann-Sträussler-Scheinker disease. Sixty-four patients exhibited progressive ataxia, dementia, and parkinsonian features. Inheritance appears to be autosomal dominant. Impaired smooth-pursuit eye movements, defective short-term memory, clumsiness of the hands, and ataxia of gait develop in the late 30s to early 60s. Eye movement abnormalities are characteristic of cerebellar dysfunction. Dementia progresses gradually over several years. Later, rigidity and bradykinesia appear and, at this stage, there is often psychosis or severe depression with rapid weight loss. Death occurs in 6 months to 2 years after onset of rigidity. Magnetic resonance imaging in 2 affected individuals showed cerebellar atrophy. There is decreased T2 signal in the basal ganglia, consistent with iron deposition.

Fragile X expression in Martin-Bell syndrome, intellectually normal individuals, and neoplasia, interpreted by a viral hypothesis.

We present data on fragile X expression in lymphocytes obtained from the following patients: a university student, an infertile couple, 6 of 22 prostatic cancer patients, a meningioma patient, and members of families with meningioma and familial gliomas. All patients were of normal intelligence. In addition, we report 3 cases of central nervous system (CNS) tumors in more typical fragile X families. We suggest that the fragile X expression as well as the clinical findings may be caused by a viral (or similar) infection. The virus may require a receptor protein coded by one allele of a gene on the X chromosome.

[Epidemiological research in amyotrophic leukospongiosis]. / Epidemiologicheskie issledovaniia pri amiotroficheskom leikospongioze.

The epidemiological aspects of amyotrophic leukospongiosis (AL), a slow viral infection of the central nervous system leading to the fatal outcome in 2-4 years, have been studied. As a rule, this disease is observed in the inhabitants of rural areas or in town dwellers born in rural areas and having spent there a considerable part of their life. AL occurs in persons of middle and older age; young people under 19 years and old people over 68 years of age are not affected by this infection. In contrast to amyotrophic lateral sclerosis and the Jakob-Creutzfeldt disease, AL is characteristic for persons in the phase of hormonal activity. The disease starts mostly in autumn and winter; this regularity is especially pronounced in women. The morbidity level (according to the average annual data) is at present 0.3 per million of population. An increased morbidity rate is characteristic of the family and group type of the epidemic process. This higher morbidity rate, by one order higher than that observed in the sporadic type of morbidity, is caused by the gradual formation of "genetic isolates".

Gerstmann-Straüssler-Scheinker disease.

In three out of six investigated cases of familially occurring dementia in adult age, the neuropathological examination disclosed Gerstmann-Sträussler-Scheinker disease, morphologically characterized by the presence of amyloid plaques and spongy condition of the brain grey matter. The spongy condition makes this disease related to Creutzfeldt-Jacob disease. The presence of the amyloid plaques signalizes an extreme production of the protein material which accumulates in them and which will be different from the amyloid in the senile plaques in Alzheimer's disease, and probably corresponds with infectious protein substances--prions or protein-like particles (PLP).

Gerstmann-Sträussler-Scheinker disease with coincidental familial onset.

A family with Gerstmann-Sträussler-Scheinker disease had coincidental clinical onset in three members of two generations, a phenomenon suggesting a common source of a transmissible agent. A regular dietary supplement in this family was home-bred rabbit. The clinical picture, although generally similar to that in previous accounts, included the unusual findings of visual loss (one patient) and sensory loss (one patient), and dementia was not apparent until late in the illness in two patients. Pathological examination of a cerebellar cortical biopsy specimen from one patient and postmortem tissue from two patients revealed multicentric amyloid plaques located in cerebral and cerebellar cortex, basal ganglia, and white matter with degeneration of corticospinal, dorsal spinocerebellar, dentatorubral, and geniculocalcarine tracts and dorsal columns. Spongiform change was focal and confined to the superficial cerebral cortical layers.

Creutzfeldt-Jakob disease and kuru patients lack a mutation consistently found in the Gerstmann-Sträussler-Scheinker syndrome.

We and others have recently reported that patients with the Gerstmann-Sträussler-Scheinker syndrome have a mutation at codon 102 of the gene coding for amyloid protein that accumulates in this disease. We report here that this mutation was not found in 5 familial and 27 sporadic cases of Creutzfeldt-Jakob disease or in 3 patients with kuru, so that although this mutation may be responsible for amyloidogenesis and transmissibility in Gerstmann-Sträussler-Scheinker syndrome, it cannot be the only cause of human spongiform encephalopathy.

Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome.

Gerstmann-Sträussler syndrome is a rare familial neurodegenerative condition that is vertically transmitted, in an apparently autosomal dominant way. It can also be horizontally transmitted to non-human primates and rodents through intracerebral inoculation of brain homogenates from patients with the disease. The exact incidence of the syndrome is unknown but is estimated to be between one and ten per hundred million. Patients initially suffer from ataxia or dementia and deteriorate until they die, in one to ten years. Protease-resistant prion protein (PrP) and PrP-immunoreactive amyloid plaques with characteristic morphology accumulate in the brains of these patients. Current diagnostic criteria for Gerstmann-Sträussler syndrome incorporate clinical and neuropathological features, as animal transmission studies can be unreliable. PrP is implicated in the pathogenesis and transmission of the condition and in scrapie, an equivalent animal disease. It was discovered by enriching scrapie-infected hamster brain fractions for infectivity. Because there is compelling evidence that the scrapie isoform of PrP is a necessary component of the infectious particle, it seemed possible that the PrP gene on the short arm of human chromosome 20 in Gerstmann-Sträussler syndrome might be abnormal. We show here that PrP codon 102 is linked to the putative gene for the syndrome in two pedigrees, providing the best evidence to date that this familial condition is inherited despite also being infectious, and that substitution of leucine for proline at PrP codon 102 may lead to the development of Gerstmann-Sträussler syndrome.

Experimental transmission of an autosomal dominant spongiform encephalopathy: does the infectious agent originate in the human genome?

Marmosets inoculated intracerebrally with brain tissue from a woman with Gerstmann-Straussler syndrome (an autosomal dominant dementia associated with spongiform change and amyloid deposition) developed an encephalopathy indistinguishable from that seen in marmosets inoculated with brain tissue from a typical case of Creutzfeldt-Jakob disease. As in Huntington's disease, in the pedigree of the patient with Gerstmann-Straussler syndrome women who subsequently developed the illness had increased fecundity. The pathogen in human transmissible dementia may arise from a sequence (which itself sometimes confers a selective advantage) located within the human genome.