D. Carleton Gajdusek

Hypothesis: interference with axonal transport of neurofilament as a common pathogenetic mechanism in certain diseases of the central nervous system.

The cytoskeletons of all cells contain three ultrastructurally distinct elements made of fibrous macromolecules: microtubules 24 nm in diameter, intermediate filaments 10 nm in diameter, and microf...

Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome

A host protein encoded by the gene specifying the scrapie amyloid precursor affects pathogenesis of the transmissible spongiform encephalopathies: Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinkers syndrome (GSS), and kuru in man, and scrapie in animals. We found a mutation in this gene of two patients with CJD from one family and a second mutation in the same gene in three patients with GSS from another family. The mutation in two related familial CJD patients changed glutamine in position 200 tolysine. This mutation was absent in other individuals including unrelated patients with familial CJD, sporadic CJD, and GSS. The other mutation in three GSS patients changed proline in position 102 to leucine, the same mutation described recently in some GSS families. We did not find it in six unaffected relatives of the GSS patients or in other individuals including sporadic and familial CJD patients. A rare insertion described earlier in one CJD family was also absent in all tested individuals.

Abnormal Proteins in the Cerebrospinal Fluid of Patients with Creutzfeldt–Jakob Disease

We studied more than 300 cerebrospinal fluid proteins from 21 patients with Creutzfeldt-Jakob disease. We also examined cerebrospinal fluid from 100 normal controls and more than 400 patients with various neurologic disorders other than Creutzfeldt-Jakob disease. Four abnormal proteins that were identified in the patients with Creutzfeldt-Jakob disease were absent in the normal persons. Two of these proteins (Mr [relative molecular mass], 40,000; pl [isoelectric point], 5.7 and Mr 40,000; pl 5.9) were also present in some patients with multiple sclerosis, herpes simplex encephalitis, schizophrenia, Parkinsons disease, or Guillain-Barré or Behçets syndrome. Two proteins (Mr 26,000; pl 5.2 and Mr 29,000; pl 5.1) were present in all patients with Creutzfeldt-Jakob disease and in 5 of 10 patients with herpes simplex encephalitis, but in none of the other control groups. A subsequent blinded study of these cerebrospinal fluid proteins from patients with Creutzfeldt-Jakob disease, Alzheimers disease, Huntingtons disease, multi-infarct dementia, parkinsonism dementia of Guam, or the specific dementia of the acquired immunodeficiency syndrome resulted in the ability to distinguish all cases of Creutzfeldt-Jakob disease from the other types of dementia. Although the identity and origin of the abnormal spinal fluid proteins are not yet known, these preliminary results suggest that their presence may help in the diagnosis of Creutzfeldt-Jakob disease.

Virus Hemorrhagic Fevers. Special reference to Hemorrhagic Fever with Renal Syndrome (Epidemic Hemorrhagic Fever).

Summary Virus hemorrhagic fevers are being described from many parts of the world. The incidence of these disorders among children and adolescents has varied considerably in the different outbreaks. Cases among children were especially frequent in the mosquito-borne hemorrhagic fevers recently reported from the Far East. Children are more frequently infected with all of these agents than has been realized. The present synthesis attempts to clarify the numerous terms used to designate hemorrhagic fevers, to place these syndromes of acute infectious arthropod-transmitted virus diseases with associated hemorrhagic diatheses into proper relation with other common infectious diseases of childhood, and to suggest a less ambiguous classification than that currently used. The most important of these diseases, hemorrhagic fever with renal syndrome, is described in some detail. More complete descriptions of other hemorrhagic fevers will be presented in a further publication.

Diagnosis of Creutzfeldt-Jakob Disease by Western Blot Identification of Marker Protein in Human Brain Tissue

We tested purified preparations of brain tissue from 39 patients with Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, or kuru, and from 32 patients with a variety of nonspongiform degenerative diseases, with the use of Western blots against an antiserum to a similarly purified fraction made from scrapie-infected hamster brain. Positive reactions occurred in 81 percent of the 31 specimens from the patients with Creutzfeldt-Jakob disease (and in all of the 7 specimens that were stored frozen for less than one year), in 3 of the 4 specimens from the patients with kuru, in 3 of the 4 specimens from the patients with Gerstmann-Sträussler-Scheinker syndrome, and in none of the specimens from the patients with other neurologic degenerative disorders, including familial or sporadic Alzheimers disease; dementia associated with myoclonus, motor neuron disease, or parkinsonism; and acquired-immunodeficiency-syndrome encephalopathy. Immunologic testing has thus begun to provide a useful and rapid adjunct to neuropathological examinations and animal-transmission experiments for the diagnosis of the spongiform encephalopathies.

Chemical disinfection of Creutzfeldt-Jakob disease virus.

RECOMMENDATIONS for the disinfection of virus-contaminated tissues from patients with Creutzfeldt–Jakob disease (CJD), published five years ago in the Journal, 1 relied heavily on data from experim...

INFECTION OF CHIMPANZEES BY HUMAN T-LYMPHOTROPIC RETROVIRUSES IN BRAIN AND OTHER TISSUES FROM AIDS PATIENTS

The authors report the isolation of acquired immunodeficiency syndrome (AIDS) associated retroviruses from packed leukocytes of 2 chimpanzees inoculated intracerebrally and intravenously with brain tissue suspension from 2 patients with AIDS encephalopathy on days 7 and 14 after inoculation. Antibody to the AIDS-associated retroviruses has appeared in sera of 2 chimpanzees inoculated intravenously with plasma from different AIDS patients in 1 chimpanzee inoculated intravenously with brain and thymus suspension and in 1 chimpanzee inoculated intracerebrally with brain tissue suspension from a patient with AIDS encephalopathy. 11 chimpanzees inoculated with supernatant fluids from tissue cultures infected with human T-lymphotropic virus type III (HTLV-III) lymphadenopathy-associated virus (LAV) and IDAV have acquired antibodies to the LAV/HTLV-III viral antigens 2-8 weeks after inoculation. Virus was recovered from the lymphocytes of all 6 seroconverted animals between 8-154 days after primary inoculation of HTLV-III. 2 animals have severe suppression of T-cell function. However all 23 chimpanzees that have seroconverted to HTLV-III or LAV antigen have remained clinically well for 2-15 months of follow-up. There have been no tumors lymphadenopathy or severe opportunistuc infections. Other species of non-human primates similarly inoculated with HTLV-III and LAV have not seroconverted 2-10 months postinoculation. These findings confirm the active and persistent virus infection of chimpanzees with retroviruses derived from AIDS patients. They further establish the presence of viruses in the plasma and brain of AIDS patients by direct transmission of their virus to chimpanzees.

Precautions in medical care of, and in handling materials from, patients with transmissible virus dementia (Creutzfeldt-Jakob disease).

We have formulated a series of precautions to be observed in caring for patients with Creutzfeldt-Jakob disease and in handling their tissues. The virus resists inactivation by simple boiling in water. Also ineffective are 10 per cent formalin, 70 per cent alcohol and ionizing and ultraviolet radiation. Autoclaving for one hour at 121 degrees C and 20 psi inactivates the agent completely. Five per cent hypochlorite, 0.03 per cent permanganate, phenolics and iodine solutions are adequate disinfectants inactivating large infective doses of the virus. Special isolation wards for afflicted patients seem unwarranted. Workers exposed to infected saliva, nasopharyngeal secretions, urine or feces need to and should wash thoroughly with ordinary soap. Needles and needle electrodes should be autoclaved or incinerated and discarded. Demented persons should not be used for donations of blood or other tissues. Although precautions are necessary, the epidemiologic evidence does not suggest an unusual risk of Creutzfeldt-Jakob disease for medical workers.

Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin ☆: A clinical and genetic study

Alzheimers disease (AD) occurred in 37 individuals from two kindreds of Jewish ancestry with a mode of transmission suggesting an autosomal dominant genetic trait. Both kindreds originated from Byelorussia and spoke the Lithuanian dialect of Yiddish. In one of the two families one case of pathologically confirmed AD occurred with clinical and neuropathological signs of Parkinsons disease. In the other family one case of amyotrophic lateral sclerosis and one case of Downs syndrome occurred, both without clinical or pathological signs of AD. In the single kindred tested, a study of the chromosome 6 markers HLA, Bf and GLO failed to reveal a correlation between the transmission of AD and the segregation of these markers. The association of increased aneuploidy of peripheral blood chromosomes with AD was not confirmed in either of these families. Genetic differences between the familial and the sporadic form of AD are discussed.

Serum antibodies to neurofilament antigens in patients with neurological and other diseases and in healthy controls

A total of 529 sera from patients with a wide variety of neurological and non-neurological diseases, and 101 sera from healthy control subjects, were examined by indirect immunofluorescence for the presence of autoantibodies to neurofilament antigens. Antibodies were found in approximately 50% of sera from patients with spongiform encephalopathies, 15-30% of sera from patients with other neurological and non-neurological diseases, and 7% of sera from healthy controls. The antigenic stimulus to these autoantibodies in very diverse disease processes is unknown, but as presently assayed, they are not of sufficient specificity to be useful as an aid to clinical diagnosis.