Direct prion neuroinvasion following inhalation into the nasal cavity.

Inhalation of prions into the nasal cavity is an efficient route of infection. Following inhalation of infectious prions, animals develop disease with a similar incubation period compared with per os exposure, but with greater efficiency. To identify the reason for this increased efficiency, we identified neural structures that uniquely innervate the nasal cavity and neural structures known to mediate neuroinvasion following oral infection and used immunohistochemistry to determine the temporal and spatial accumulation of prions from hamster tissue sections containing cell bodies and axons at 2-week intervals following prion exposure.

Expression of the cellular prion protein by mast cells in white-tailed deer carotid body, cervical lymph nodes and ganglia.

Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion.

Liposomes and transferosomes in the delivery of papain for the treatment of keloids and hypertrophic scars.

Hypertrophic scars and keloids are characterized by an excessive collagen deposition. The available treatment options are invasive and can result in recurrence of scar formation. Using liposomes and transferosomes for the topical delivery of papain, a proteolytic enzyme, can be effective treatment.

Expression of the cellular prion protein by mast cells in the human carotid body.

Prion diseases are fatal neurologic disorders that can be transmitted by blood transfusion. The route for neuroinvasion following exposure to infected blood is not known. Carotid bodies (CBs) are specialized chemosensitive structures that detect the concentration of blood gasses and provide feedback for the neural control of respiration.

Transport of Prions in the Peripheral Nervous System: Pathways, Cell Types, and Mechanisms.

Prion diseases are transmissible protein misfolding disorders that occur in animals and humans where the endogenous prion protein, PrP, undergoes a conformational change into self-templating aggregates termed PrP. Formation of PrP in the central nervous system (CNS) leads to gliosis, spongiosis, and cellular dysfunction that ultimately results in the death of the host. The spread of prions from peripheral inoculation sites to CNS structures occurs through neuroanatomical networks.

The Role of the Nasal Cavity in the Pathogenesis of Prion Diseases.

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a class of fatal neurodegenerative diseases caused by the entry and spread of infectious prion proteins (PrP) in the central nervous system (CNS). These diseases are endemic to certain mammalian animal species that use their sense of smell for a variety of purposes and therefore expose their nasal cavity (NC) to PrP in the environment. Prion diseases that affect humans are either inherited due to a mutation of the gene that encodes the prion protein, acquired by exposure to contaminated tissues or medical devices, or develop without a known cause (referred to as ).

Efficient interspecies transmission of synthetic prions.

Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission.

Characterization and Systemic Delivery of Dibenzoylmethane via the Intranasal Route.

Intranasal (IN) administration is known to be noninvasive with the potential to carry a drug or vaccine directly to the blood, bypassing first-pass metabolism in the liver and the harsh environment of the gastrointestinal system. Orally administered dibenzoylmethane (DBM) has been shown experimentally to be neuroprotective in animal models of tauopathy and prion disease and effective in the treatment of certain forms of cancers. The purpose of this study was to prepare, characterize, and test formulations of DBM designed for IN administration.

Failure To Detect Prion Infectivity in Ticks following Prion-Infected Blood Meal.

Chronic wasting disease (CWD) is an emerging and fatal contagious prion disease that affects cervids, including mule deer, white-tailed deer, black-tailed deer, red deer reindeer, elk, and moose. CWD prions are widely distributed throughout the bodies of CWD-infected animals and are found in the nervous system, lymphoid tissues, muscle, blood, urine, feces, and antler velvet. The mechanism of CWD transmission in natural settings is unknown.

Enhanced neuroinvasion by smaller, soluble prions.

Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves.

PrPSc formation and clearance as determinants of prion tropism.

Prion strains are characterized by strain-specific differences in neuropathology but can also differ in incubation period, clinical disease, host-range and tissue tropism. The hyper (HY) and drowsy (DY) strains of hamster-adapted transmissible mink encephalopathy (TME) differ in tissue tropism and susceptibility to infection by extraneural routes of infection. Notably, DY TME is not detected in the secondary lymphoreticular system (LRS) tissues of infected hosts regardless of the route of inoculation.

Incongruity between Prion Conversion and Incubation Period following Coinfection.

Unlabelled: When multiple prion strains are inoculated into the same host, they can interfere with each other. Strains with long incubation periods can suppress conversion of strains with short incubation periods; however, nothing is known about the conversion of the long-incubation-period strain during strain interference. To investigate this, we inoculated hamsters in the sciatic nerve with long-incubation-period strain 139H prior to superinfection with the short-incubation-period hyper (HY) strain of transmissible mink encephalopathy (TME).

Immediate and Ongoing Detection of Prions in the Blood of Hamsters and Deer following Oral, Nasal, or Blood Inoculations.

Infectious prions traverse epithelial barriers to gain access to the circulatory system, yet the temporal parameters of transepithelial transport and persistence in the blood over time remain unknown. We used whole-blood real-time quaking-induced conversion (wbRT-QuIC) to analyze whole blood collected from transmissible spongiform encephalopathy (TSE)-inoculated deer and hamsters throughout the incubation period for the presence of common prion protein-conversion competent amyloid (PrPCCCA). We observed PrPC-CCA in the blood of TSE-inoculated hosts throughout the disease course from minutes postexposure to terminal disease.

Nasal associated lymphoid tissue of the Syrian golden hamster expresses high levels of PrPC.

The key event in the pathogenesis of the transmissible spongiform encephalopathies is a template-dependent misfolding event where an infectious isoform of the prion protein (PrPSc) comes into contact with native prion protein (PrPC) and changes its conformation to PrPSc. In many extraneurally inoculated models of prion disease this PrPC misfolding event occurs in lymphoid tissues prior to neuroinvasion. The primary objective of this study was to compare levels of total PrPC in hamster lymphoid tissues involved in the early pathogenesis of prion disease.

In vitro detection of prionemia in TSE-infected cervids and hamsters.

Blood-borne transmission of infectious prions during the symptomatic and asymptomatic stages of disease occurs for both human and animal transmissible spongiform encephalopathies (TSEs). The geographical distribution of the cervid TSE, chronic wasting disease (CWD), continues to spread across North America and the prospective number of individuals harboring an asymptomatic infection of human variant Creutzfeldt-Jakob Disease (vCJD) in the United Kingdom has been projected to be ~1 in 3000 residents. Thus, it is important to monitor cervid and human blood products to ensure herd health and human safety.

Rapid transepithelial transport of prions following inhalation.

Prion infection and pathogenesis are dependent on the agent crossing an epithelial barrier to gain access to the recipient nervous system. Several routes of infection have been identified, but the mechanism(s) and timing of in vivo prion transport across an epithelium have not been determined. The hamster model of nasal cavity infection was used to determine the temporal and spatial parameters of prion-infected brain homogenate uptake following inhalation and to test the hypothesis that prions cross the nasal mucosa via M cells.

The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease.

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrP(Sc), is an essential component of the infectious agent, the strain-specific relationship between PrP(Sc) properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrP(Sc) from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrP(Sc) in neurons and glia.

Coinfecting prion strains compete for a limiting cellular resource.

Prion strain interference can influence the emergence of a dominant strain from a mixture; however, the mechanisms underlying prion strain interference are poorly understood. In our model of strain interference, inoculation of the sciatic nerve with the drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent prior to superinfection with the hyper (HY) strain of TME can completely block HY TME from causing disease. We show here that the deposition of PrP(Sc), in the absence of neuronal loss or spongiform change, in the central nervous system corresponds with the ability of DY TME to block HY TME infection.

Prion strain targeting independent of strain-specific neuronal tropism.

While neuropathological features that define prion strains include spongiform degeneration and deposition patterns of PrP(Sc), the underlying mechanism for the strain-specific differences in PrP(Sc) targeting is not known. To investigate prion strain targeting, we inoculated hamsters in the sciatic nerve with either the hyper (HY) or drowsy (DY) strain of the transmissible mink encephalopathy (TME) agent. Both TME strains were initially retrogradely transported in the central nervous system (CNS) exclusively by four descending motor tracts.

Long-term safety evaluation of a novel oxygen-coordinated niacin-bound chromium (III) complex.

Chromium (III) is an essential micronutrient required for normal protein, fat and carbohydrate metabolism, as well as helps insulin metabolize fat, turn protein into muscle and convert sugar into energy. A broad spectrum of research investigations including in vitro, in vivo and clinical studies demonstrated the beneficial effects of novel oxygen- coordinated niacin-bound chromium (III) complex (NBC) in promoting glucose-insulin sensitivity, lipid profile, cardioprotective ability and lean body mass. This study examined the long-term safety of NBC by orally administering either 0 or 25 ppm or the human equivalency dose of 1000 microg elemental chromium (III) as NBC per day for 52 consecutive weeks to male and female Sprague-Dawley rats.

The nasal cavity is a route for prion infection in hamsters.

Animals that naturally acquire the prion diseases have a well-developed olfactory sense that they utilize for a variety of basic behaviors. To assess the potential for the nasal cavity to serve as a point of entry for prion diseases, a small amount of prion-infected brain homogenate was placed inferior to the nostrils of hamsters, where it was immediately sniffed into the nasal cavity. Hamsters extra-nasally inoculated with the HY strain of transmissible mink encephalopathy (TME) agent had an incubation period that was not significantly different from per os inoculation of the same dose of the HY TME agent.

Prion interference is due to a reduction in strain-specific PrPSc levels.

When two prion strains infect a single host, one strain can interfere with the ability of the other to cause disease but it is not known whether prion replication of the second strain is also diminished. To further investigate strain interference, we infected hamsters in the sciatic nerve with the long-incubation-period transmissible mink encephalopathy (TME) agent DY TME prior to superinfection of hamsters with the short-incubation-period HY TME agent. Increases in the interval between TME agent inoculations resulted in an extension of the incubation period of HY TME or a complete block of the ability of the HY TME agent to cause disease.

Interspecies transmission of chronic wasting disease prions to squirrel monkeys (Saimiri sciureus).

Chronic wasting disease (CWD) is an emerging prion disease of deer and elk. The risk of CWD transmission to humans following exposure to CWD-infected tissues is unknown. To assess the susceptibility of nonhuman primates to CWD, two squirrel monkeys were inoculated with brain tissue from a CWD-infected mule deer.

Safety and toxicological evaluation of a novel niacin-bound chromium (III) complex.

Chromium is an essential trace element required for normal protein, fat and carbohydrate metabolism. It also helps in energy production and increasing lean body mass. Niacin-bound chromium (NBC) is a unique form of bioavailable chromium that promotes healthy lipid profile.

Extraneural prion neuroinvasion without lymphoreticular system infection.

While prion infection of the lymphoreticular system (LRS) is necessary for neuroinvasion in many prion diseases, in bovine spongiform encephalopathy and atypical cases of sheep scrapie there is evidence to challenge that LRS infection is required for neuroinvasion. Here we investigated the role of prion infection of LRS tissues in neuroinvasion following extraneural inoculation with the HY and DY strains of the transmissible mink encephalopathy (TME) agent. DY TME agent infectivity was not detected in spleen or lymph nodes following intraperitoneal inoculation and clinical disease was not observed following inoculation into the peritoneum or lymph nodes, or after oral ingestion.