Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt– Jakob disease: Implications for human health

There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt–Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.

Heightened expression of tumor necrosis factor alpha, interleukin 1 alpha, and glial fibrillary acidic protein in experimental Creutzfeldt-Jakob disease in mice.

The ultrastructural pathology of myelinated axons in mice infected experimentally with the Fujisaki strain of Creutzfeldt-Jakob disease (CJD) virus is characterized by myelin sheath vacuolation that closely resembles that induced in murine spinal cord organotypic cultures by tumor necrosis factor alpha (TNF-alpha), a cytokine produced by astrocytes and macrophages. To clarify the role of TNF-alpha in experimental CJD, we investigated the expression of TNF-alpha in brain tissues from CJD virus-infected mice at weekly intervals after inoculation by reverse transcription-coupled PCR, Northern and Western blot analyses, and immunocytochemical staining. Neuropathological findings by electron microscopy, as well as expression of interleukin 1 alpha and glial fibrillary acidic protein, were concurrently monitored. As determined by reverse transcription-coupled PCR, the expression of TNF-alpha, interleukin 1 alpha, and glial fibrillary acidic protein was increased by approximately 200-fold in the brains of CJD virus-inoculated mice during the course of disease. By contrast, beta-actin expression remained unchanged. Progressively increased expression of TNF-alpha in CJD virus-infected brain tissues was verified by Northern and Western blot analyses, and astrocytes in areas with striking myelin sheath vacuolation were intensely stained with an antibody against murine TNF-alpha. The collective findings of TNF-alpha overexpression during the course of clinical disease suggest that TNF-alpha may mediate the myelin sheath vacuolation observed in experimental CJD.

Viral particles are required for infection in neurodegenerative Creutzfeldt-Jakob disease.

Several models have been proposed for the infectious agents that cause human Creutzfeldt-Jakob disease (CJD) and sheep scrapie. Purified proteins and extracted nucleic acids are not infectious. To further identify the critical molecular components of the CJD agent, 120S infectious material with reduced prion protein (PrP) was treated with guanidine hydrochloride or SDS. Particulate and soluble components were then separated by centrifugation and molecularly characterized. Conditions that optimally solubilized residual PrP and/or nucleic acid-protein complexes were used to produce subfractions that were assayed for infectivity. All controls retained > 90% of the 120S titer (approximately 15% of that in total brain) but lost > 99.5% of their infectivity after heat-SDS treatment (unlike scrapie fractions enriched for PrP). Exposure to 1% SDS at 22 degrees C produced particulate nucleic acid-protein complexes that were almost devoid of host PrP. These sedimenting complexes were as infectious as the controls. In contrast, when such complexes were solubilized with 2.5 M guanidine hydrochloride, the infectious titer was reduced by > 99.5%. Sedimenting PrP aggregates with little nucleic acid and no detectable nucleic acid-binding proteins had negligible infectivity, as did soluble but multimeric forms of PrP. These data strongly implicate a classical viral structure, possibly with no intrinsic PrP, as the CJD infectious agent. CJD-specific protective nucleic acid-binding protein(s) have already been identified in 120S preparations, and preliminary subtraction studies have revealed several CJD-specific nucleic acids. Such viral candidates deserve more attention, as they may be of use in preventing iatrogenic CJD and in solving a fundamental mystery.

Gauger's certificate, 1785 September 10

One-page handwritten document certifying Caleb Hayden was taught the art of gauging.

Will of the Rev. Andrew Croswell, 1785 November

This folder contains three handwritten copies of the November 8, 1785, will of Andrew Croswell and a copy of the inventory of Croswell's estate.

Accounts with Benjamin Huntington, 1785-1787

This folder contains two handwritten copies of the accounts between Reverend Andrew Croswell of Boston, and Croswell's executor William Croswell, and Benjamin Huntington, for money collected from Col. Gallup between 1785 and 1787.

Receipts related to the dispersal of the Croswell estate, 1785-1788

Seven handwritten receipts dated between 1785 and 1788.

Financial bills and receipts, 1785-1786

This folder contains eight bills and receipts including five receipts for payment by William Croswell for the costs of boarding Croswell's brother Nathaniel.

C. Tax bills, 1785-1805

This subseries contains ten printed tax bills filled out in manuscript for William Croswell between 1785 and 1805.

The constitution and laws of the Adelphoi Theologia, founded 1785, [1785-1847]

The volume includes manuscript versions of the constitution and laws from 1785, 1832, and amendments, as well as a list of members from the Class of 1786 through the Class of 1847.

Payment order for Thomas Adams, 1785 June 30

Handwritten order to John Sale to pay scholarship funds to student Thomas Adams (Harvard AB 1788), signed by signed by Charles Chauncey, John Clarke, Jonathan Williams, and James Thwing.

Quarter bill for Timothy Bigelow, 1785 February 25

Printed quarter bill for Timothy Bigelow (Harvard AB 1786) with sizing and punishment totals. Handwritten text of name, date, and bill totals is faded.

Bond for David Cowing. 1785 November 16

Printed bond of James Cowing, Shoemaker and Timothy Doty, yeoman of Ballstown, New York to the President and Fellows of Harvard College for 200 ounces of silver on behalf of student David Cowing. The bond was witnessed by Samuel Randall and Lettes Jenne.

Bond between John Leverett and Elisha Cooke to John White, Treasurer of Harvard College, 1716 November 20

Two folio-sized leaves containing a one-and-a-half page copy of the bond between John Leverett and Elisha Cooke to John White, Treasurer of Harvard, for £200. The bond was witnessed by William Austin and Mary Gilbert. An October 3, 1726 receipt of payment from Nathaniel Byfield on the bond, signed by Treasurer Edward Hutchinson, is located on the verso of the first leaf.