Diagnosis Of Preclinical Disease Research Articles

The Gut-Associated Lymphoid Tissues in the Small Intestine, Not the Large Intestine, Play a Major Role in Oral Prion Disease Pathogenesis.

ABSTRACTPrion diseases are infectious neurodegenerative disorders characterized by accumulations of abnormally folded cellular prion protein in affected tissues. Many natural prion diseases are acquired orally, and following exposure, the early replication of some prion isolates upon follicular dendritic cells (FDC) within gut-associated lymphoid tissues (GALT) is important for the efficient spread of disease to the brain (neuroinvasion). Prion detection within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, the relative contributions of the small and large intestinal GALT to oral prion pathogenesis were unknown. To address this issue, we created mice that specifically lacked FDC-containing GALT only in the small intestine. Our data show that oral prion disease susceptibility was dramatically reduced in mice lacking small intestinal GALT. Although these mice had FDC-containing GALT throughout their large intestines, these tissues were not early sites of prion accumulation or neuroinvasion. We also determined whether pathology specifically within the large intestine might influence prion pathogenesis. Congruent infection with the nematode parasite Trichuris muris in the large intestine around the time of oral prion exposure did not affect disease pathogenesis. Together, these data demonstrate that the small intestinal GALT are the major early sites of prion accumulation and neuroinvasion after oral exposure. This has important implications for our understanding of the factors that influence the risk of infection and the preclinical diagnosis of disease.IMPORTANCE Many natural prion diseases are acquired orally. After exposure, the accumulation of some prion diseases in the gut-associated lymphoid tissues (GALT) is important for efficient spread of disease to the brain. However, the relative contributions of GALT in the small and large intestines to oral prion pathogenesis were unknown. We show that the small intestinal GALT are the essential early sites of prion accumulation. Furthermore, congruent infection with a large intestinal helminth (worm) around the time of oral prion exposure did not affect disease pathogenesis. This is important for our understanding of the factors that influence the risk of prion infection and the preclinical diagnosis of disease. The detection of prions within large intestinal GALT biopsy specimens has been used to estimate human and animal disease prevalence. However, our data suggest that using these biopsy specimens may miss individuals in the early stages of oral prion infection and significantly underestimate the disease prevalence.

Продукція діабетасоційованих аутоантитіл до острівцевих аутоантигенів (IAB2A, GADA, IAA) у дітей і підлітків на етапах еволюції цукрового діабету 1 типу як основа клініко-імунологічного алгоритму доклінічної діагностики захворювання

Продукція діабетасоційованих аутоантитіл до острівцевих аутоантигенів (IAB2A, GADA, IAA) у дітей і підлітків на етапах еволюції цукрового діабету 1 типу як основа клініко-імунологічного алгоритму доклінічної діагностики захворювання

Transformer la médecine et la santé par la découverte Les grandes orientations en recherche biomédicale

The NIH, which originated from the Marine Hospital Laboratory of Hygiene (1887), was established as the national agency for medical research by President F. D. Roosevelt in 1944. The NIH rests on its independent, world-class peer review process and its distinctive scientific and public advisory structure. The two-fold mission of NIH is to define research priorities based on public health needs and to allocate funding. Eighty-four percent of the budget supports 300,000 extramural scientists and research workers at more than 3,000 universities. Only 16% of the budget is spent within the NIH itself (on administration and the 27 institutes and centers, including some 10,000 intramural scientists, that make up NIH today). The ecosystem of science and biotechnology connects NIH, the public, Congress, universities, the FDA, industry, and investors. The budget, which in 2007 was $29 billion, is submitted to Congress by the Director. The impact of biomedical research over the last 30 years is demonstrated by an increase in life expectancy anda decrease in death and disability from many diseases. Five evolving challenges in public health include acute conditions becoming chronic, the aging of the population, health disparities, emerging or re-emerging infectious diseases, and emerging non-communicable diseases (obesity, mental illness). Medical strategies must clearly be transformed for the 21st century. Molecular diagnosis of preclinical disease is the paradigm of the future: intervening before symptoms appear because the preclinical molecular events are known and because we have the ability to detect at-risk patients constitutes the "future paradigm of the 4 P's." Currently, the fundamental scientific barrier is our limited understanding of the complexity of biologic networks. New theoretical concepts are needed in this "hardware-to-software phase." Any roadmap for the acceleration of medical discovery will have to integrate new pathways, future research teams, and the restructuring of clinical research.

The use of non-prion biomarkers for the diagnosis of Transmissible Spongiform Encephalopathies in the live animal

Scrapie and bovine spongiform encephalopathy (BSE) are major global concerns and the emergence of variant Creutzfeldt-Jakob disease (vCJD) has caused turmoil for blood transfusion services and hospitals worldwide. Recent reports of iatrogenic CJD (iCJD) cases following blood transfusions from Transmissible Spongiform Encephalopathies (TSE)-infected donors have fuelled this concern. Major diagnostic tests for BSE and scrapie are conducted post-mortem from animals in late stages of the disease. Although the lymphoreticular system is involved in the earlier pathogenesis of some forms of sheep scrapie and vCJD, which presents great opportunity for diagnostic development, other TSE diseases (some strains of scrapie, sporadic CJD (sCJD) and bovine BSE) do not present such a diagnostic opportunity. Thus, there is an urgent need for pre-mortem tests that differentiate between healthy and diseased individuals at early stages of illness, in accessible samples such as blood and urine using less invasive procedures. This review reports on the current state of progress in the development and use of prion and non-prion biomarkers in the diagnosis of TSE diseases. Some of these efforts have concentrated on improving the sensitivity of PrPSc detection to allow in vivo diagnosis at low abundances of PrPSc whilst others have sought to identify non-prion protein biomarkers of TSE disease, many of which are still at early stages of development. In this review we comment upon the limitations of prion based tests and review current research on the development of tests for TSE that rely on non-prion disease markers in body fluids that may allow preclinical disease diagnosis.