A random-primed complementary DNA library was constructed from plasma containing the uncharacterized non-A, non-B hepatitis (NANBH) agent and screened with serum from a patient diagnosed with NANBH. A complementary DNA clone was isolated that was shown to encode an antigen associated specifically with NANBH infections. This clone is not derived from host DNA but from an RNA molecule present in NANBH infections that consists of at least 10,000 nucleotides and that is positive-stranded with respect to the encoded NANBH antigen. These data indicate that this clone is derived from the genome of the NANBH agent and are consistent with the agent being similar to the togaviridae or flaviviridae. This molecular approach should be of great value in the isolation and characterization of other unidentified infectious agents.

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Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome

After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

http://science.sciencemag.org/content/sci/216/4542/136.full.pdf

Novel proteinaceous infectious particles cause scrapie

Objective. To standardize outcome measures in systemic lupus erythematosus (SLE). Three indices were identified which could adequately describe outcome (disease activity, damage from disease, and health status); we describe here the development of the Disease Activity Index.

Methods. Twenty-four variables were identified as important factors in a disease activity index. These were used to generate 574 patient profiles, which were rated on a disease activity scale of 0–10 by 14 rheumatologists. A second rating of 10 of the profiles yielded scores that were not significantly different from the first, indicating that experienced clinicians can reliably make global estimates of disease activity. Multiple regression models were used to estimate the relative importance of the 24 clinical variables in the physicians' global rating of disease activity. These were estimated on a ‘training set’ of 75% of physicians' ratings, and then validated on a ‘testing set,’ consisting of the remaining 25% of physicians' ratings.

Results. The explanatory power of the models in the training set was high (R2 = 0.93). The models' regression coefficients for the organ systems were simplified for easier use in clinical practice. This generated a ‘weighted’ index of 9 organ systems for disease activity in SLE, the SLEDAI, as follows: 8 for central nervous system and vascular, 4 for renal and musculoskeletal, 2 for serosal, dermal, immunologic, and 1 for constitutional and hematologic. The maximum theoretical score is 105, but in practice, few patients have scores greater than 45. The SLEDAI predicted well the physicians' ratings in the testing set (Pearson's correlation coefficients = 0.64–0.79).

Conclusion. The SLEDAI is a validated model of experienced clinicians' global assessments of disease activity in lupus. It represents the consensus of a group of experts in the field of lupus research.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.1780350606

Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE.

First-order nonlinear differential-delay equations describing physiological control systems are studied. The equations display a broad diversity of dynamical behavior including limit cycle oscillations, with a variety of wave forms, and apparently aperiodic or "chaotic" solutions. These results are discussed in relation to dynamical respiratory and hematopoietic diseases.

https://science.sciencemag.org/content/sci/197/4300/287.full.pdf

Oscillation and Chaos in Physiological Control Systems

A specific assay has been developed for a blood-borne non-A, non-B hepatitis (NANBH) virus in which a polypeptide synthesized in recombinant yeast clones of the hepatitis C virus (HCV) is used to capture circulating viral antibodies. HCV antibodies were detected in six of seven human sera that were shown previously to transmit NANBH to chimpanzees. Assays of ten blood transfusions in the United States that resulted in chronic NANBH revealed that there was at least one positive blood donor in nine of these cases and that all ten recipients seroconverted during their illnesses. About 80 percent of chronic, post-transfusion NANBH (PT-NANBH) patients from Italy and Japan had circulating HCV antibody; a much lower frequency (15 percent) was observed in acute, resolving infections. In addition, 58 percent of NANBH patients from the United States with no identifiable source of parenteral exposure to the virus were also positive for HCV antibody. These data indicate that HCV is a major cause of NANBH throughout the world.

https://science.sciencemag.org/content/sci/244/4902/362.full.pdf

An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis

Danazol, an androgen derivative, was evaluated for its effectiveness in preventing attacks of hereditary angioedema in a double-blind study with nine patients. Of 47 placebo courses, 44 ended with attacks, but during 46 danazol courses only one attack occurred. Side effects were minimal, and virilization was not observed in the women studied. C1 esterase inhibitor levels increased three to four times, and levels of the fourth component of complement (C4) increased 15 times. These changes began during the first day of therapy and were maximal by one to two weeks. After therapy was stopped, C1 esterase inhibitor and C4 levels rapidly decreased. Danazol effectively prevents attacks in hereditary angioedema and acts to correct the underlying biochemical abnormality. (N Engl J Med 295:1444–1448, 1976)

Treatment of Hereditary Angioedema with Danazol

Background Chronic granulomatous disease is a rare disorder in which the phagocytes fail to produce hydrogen peroxide. The patients are predisposed to bacterial and fungal infections. Prophylactic antibiotics and interferon gamma have reduced bacterial infections, but there is also the danger of life-threatening fungal infections. We assessed the efficacy of itraconazole as prophylaxis against serious fungal infections in chronic granulomatous disease. Methods Thirty-nine patients at least 5 years old (6 female and 33 male; mean age, 14.9 years) were enrolled in a randomized, double-blind, placebo-controlled study. After the initially assigned treatment, each patient alternated between itraconazole and placebo annually. Patients 13 years of age or older and all patients weighing at least 50 kg received a single dose of 200 mg of itraconazole per day; those less than 13 years old or weighing less than 50 kg received a single dose of 100 mg per day. The primary end point was severe fungal infection, as dete...

Itraconazole to prevent fungal infections in chronic granulomatous disease.

Eleven patients with long standing familial Mediterranean fever were studied in a double-blind trial using daily colchicine or placebo. During 60 courses of placebo, 38 attacks of familial...

Colchicine therapy for familial mediterranean fever. A double-blind trial.

The relationship between the presence of antibody to hepatitis B core antigen (anti-HBc) in donor blood and the development of hepatitis in recipients of that blood was studied in 6293 blo...

Antibody to Hepatitis B Core Antigen as a Paradoxical Marker for Non-A, Non-B Hepatitis Agents in Donated Blood

The age-specific seroprevalence of antibody to hepatitis A virus (HAV) and antibody to hepatitis E virus (HEV) were studied in persons in Pune, India, where both viruses are endemic. The data showed that HAV infected the majority of persons by age 3 years and virtually 100% by late childhood. In contrast, infection with HEV was rare in children and did not reach peak prevalence (33%-40%) until early adulthood. The reason for the differences in infection rates between HAV and HEV is not known. Age-specific antibody patterns in serum samples obtained 10 years apart show that neither HAV nor HEV has diminished in medical importance in this Indian community.

https://www.jstor.org/stable/info/30132040

David W. Alling

Papers

Treatment of Hereditary Angioedema with Danazol

Itraconazole to prevent fungal infections in chronic granulomatous disease.

Colchicine therapy for familial mediterranean fever. A double-blind trial.

Antibody to Hepatitis B Core Antigen as a Paradoxical Marker for Non-A, Non-B Hepatitis Agents in Donated Blood

Age-Specific Prevalence of Antibodies to Hepatitis A and E Viruses in Pune, India, 1982 and 1992