Questions to control the knowledge

1. Signs of differentiation of viral infections and rickettsioses from bacterial infections.

2. Etiology, pathogenesis, morphological characteristics of influenza; its complications and outcomes.

3. Kinds of typhous vasculites.

4. Cause of death in patients with rabies.

5. Forms of smallpox, their morphology.

6. Malaria: pathogenesis and anatomic pathology, causes of death.

Terminology

Toxic influenza, influenza with impairment of respiratory tract, «large motley influenzal lung»; pustular smallpox, haemorrhagic smallpox, varioloid, «balloon degeneration» of epidermis, purpuric smallpox; rabies (nodules of rabies, Babes-Negri bodies); classical typhus (vasculites: warty, proliferative, necrotic; destructive-proliferative endothrombovasculitis, Popov's granulomas); malaria splenomegaly, malaria coma, Dyurk's granuloma.

PRION DISEASES (TRANSMISSIBLE

SPONGIFORM DEGENERATION

ENCEPHALOPATHIES)

Prion diseases is a group of diseases, caused by albuminous molecules (prion). At handing to him of the Nobel Prize (1997) for discovering prions, Stanly Prusiner said that prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases.

It is known that prion diseases fall into group of so-called «slow virus infections)). The term «Slow viruses» was introduced in 1954 by B. Sigurdsson for scrapie in sheep. Five years later William Hadlow used this term for kuru disease and 7 years later Igor Klatzo suspected, that Creutzfeldt-Jakob disease (CJD) of humans is slow virus disease as well.

The first information about Bovine spongiform encephalopathy as a prion disease appeared in 1982— 1986. In June 1987 the management of state veterinary medicine of Great Britain officially informed International Epizootic Office (IEO) on originating a new disease — Bovine spongiform encephalopathy. The first epidemic of Bovine spongiform encephalopathy began in Great Britain in 1986, having struck for two years about 200 thousand animal.

Besides Bovine spongiform encephalopathy, there are following prion diseases: scrapie of sheep, transmissible encephalopathy of minks, chronic exhausting illness of deer, and also disease of the people in this group of the diseases.

The special alert of sociability was called by cases of transmission of infection to the person, who not only ate infected meat but also looked for infected animals. It is known, that the shepherds more often suffer from Creutzfeldt-Jakob disease.

The incidence of the disease (per 1 million) is: Great Britain — 0.86, France — 0.76, USA — 0.83, Italy — 0.53, Holland — 0.90, Romania — 0.88, Germany — 0.6—0.8. In 1986—2000 in England the death rate from Creutzfeldt-Jakob disease was 80 persons. In France for 1979—1994 the death rate from Creutzfeldt-Jakob disease was 900 persons. In Russia there are data about 14 cases of Creutzfeldt-Jakob disease

According to the modern classification besides Creutzfeldt-Jakob disease there are the following human prion diseases or Transmissible spongiform degeneration encephalopathies — kuru disease, syndrome of Gerstmann-Straussler-Sheinker, fatal familiar insomnia, Alpers disease.

First epidemic of kuru was noted in New Guinea, having a strange, from the point of view of Europeans, custom to eat the organs of the died relatives. Women and children ate brain and men ate muscles. Thus women and children suffered from kuru more frequent.

Etiology. The causative agent of prion diseases was established in 1982 by an American scientist, Stanly Prusiner. For this he was awarded the Nobel Prize in 1997. The term «prion» originates from proteinaceous infectious particle + on. Pathological form of prion protein S.Prusiner was called PrP-Sc. Now it is known, that prion is protein in a special condition. It is interesting that prion does not have genes and consists only of changed own albuminous molecules of the host. Prion does not contain nucleic acids and, thus, differs from other microorganisms (bacteria, fungi, viruses). 20 different mutations of a gene PrP of the person have been established, thus there are 20 prion diseases, but we have knowledge only about 6.

Prion consists approximately of 254 amino acids.

Normally prion laces on a cellular membrane. However there is always a probability of spontaneous transition of normal prion to the pathogenic form. Pathologic prion differs from normal only in stereological composition of molecules.

The capacity of prion protein to give the properties and special stereological composition to normal molecules determines its infectiosity.

Prions are extremely steady. Not only cooking processes, boiling but also of X-rays, formalin fixation, aldehyde, proteinases do not destroyed them. The rendering was reached only during autoclaving at 138 °C for 1—2 hours. But at 132 °C the infection saves the properties completely.

Pathological anatomy. Macroscopical and microscopical characteristics of prion diseases have been described completely.

Macroscopically as a rule the weight of the brain is reduced, an atrophy of gyres of a brain is pronounced.

There are 4 microscopical signs in neuropathology of prion diseases:

• spongiform degeneration;

• loss of neurons;

• astrocytosis and

• formation of amyloid plaques.

Prion spongiform degeneration is characterized by formation of vacuoles from 1 up to 50 microns in diameter in the gray matter of the brain. These vacuoles can appear in different layer of a cerebral cortex. They can be isolated or they can form groups of different size. In hematoxylin and eosin staining they look like cavities with eozinofilic masses.

Spongiform degeneration, as a rule, is accompanied by reduction of the density of neurons. The degree of loss of neurons corresponds to the degree spongiform changes. Besides proliferation of astroglia is marked.

Amyloid plaques formation in the granular layer of the cortex of cerebellum is the main morphological sign of prion disease.

The spinal cord is intact visually.

Prusiner S.B. et al. (1997) have found pathologic prion in biopsies of skeletal muscles for some elderly people with progressing muscle skeletinization. Thus not only brain, but also muscles are damaged by prion.

The incubation period of prion infections lasts from 3 to 40 years, but the fatal outcome comes after manifestation of the disease within 6—12 months, depending on the kind of prion, infection dozen and reactivity of the human organism.

Clinically the following signs are characteristic for CJD: progressive destruction of intellect, visual memory disturbance, cerebellar ataxia, discoordina-tion, myoclonius (cramp of muscles or group of muscles).

Syndrome of Gerstmann-Straussler-Sheinker is characterized by cerebellar ataxia, dysphagia and dysphonia, progressing dementia.

Fatal familiar insomnia develops in 4 stages. 1 — progressing insomnia, 2 — hallucinations and periodical insomnia, 3 — full insomnia, 4 — dementia and full insomnia.

Alpers disease — is a chronic progressive encephalopathy of children, characterized by severe headache, disturbance of vision, epileptic attacks, progressive hypotonia, chronic hepatitis with cirrhosis, sometimes — hemorrhagic pancreatitis.

The main causes of death in prion diseases are cachexia, septic pneumonia.

Diagnosis. Diagnosis of prion diseases is very difficult because of absences of any prion-accotiated changes in the human fluids — blood, urine, milk.

Prions do not cause inflammatory reactions and specific antibodies are not produced. Serological reactions are useless. The most informative method is postmortem pathological anatomy investigation.

There are several modern methods of investigation which we use for identification of etiological factor of the diseases prion. They are method of Western-blotting, hystio-blotting, immuno-blotting and electronic microscopy in combination with immunohistochemical analysis.

Resent reports on methods of diagnosis.

J. Collinge (Imperial College School of Medicine, London) has discharged pathological prions from an lymphoid tissue (spleen, lymph nodes and tonsils) of the people died from CJD. It is a capability of intravital diagnosis of prion diseases in biopsy. In June, 2001 Soto etc. on murine model presented a new method permitting to reveal insignificant small doses of prions in the blood.

The method is based on amplification of transformation of normal prions in pathological, under the influence of definite sound waves.

Treatment. At handing to him of the Nobel Prize (1997) Stanly Prusiner designated probable ways of struggle with prions.

1. Creation of medicine blocking transformation of normal prion PrPc to pathological PrPSc, by stabilization normal prion with medicine.

2. Creation of medicine modifying a protein X, which is a molecular conductor at transformation of normal prion to pathological.

3. Creation of medicine destabilizing the structure of pathological prion.

What has been achieved by now?

On August 14, 2001 Carsten Korth (National Academy of Sciences of USA) reported on creation of two drugs, for treatment of prions diseases — Cunecrin and Chlorpromazinum. The drugs were used in the patients manifested infection and the condition of these patients stabilized. These drugs can remove pathological prions from the nervous cells and can restore the structure and function of these cells.