RESUMO
Venetian quarantine 400 years ago was an important public health measure. Since 1900 this has been refined to include "challenge" or deliberate infection with pathogens be they viruses, bacteria, or parasites. Our focus is virology and ranges from the early experiments in Cuba with Yellow Fever Virus to the most widespread pathogen of our current times, COVID-19. The latter has so far caused over four million deaths worldwide and 190 million cases of the disease. Quarantine and challenge were also used to investigate the Spanish Influenza of 1918 which caused over 100 million deaths. We consider here the merits of the approach, that is the speeding up of knowledge in a practical sense leading to the more rapid licensing of vaccines and antimicrobials. At the core of quarantine and challenge initiatives is the design of the unit to allow safe confinement of the pathogen and protection of the staff. Most important though is the safety of volunteers. We can see now, as in 1900, that members of our society are prepared and willing to engage in these experiments for the public good. Our ethnology study, where the investigator observed the experiment from within the quarantine, gave us the first indication of changing attitudes amongst volunteers whilst in quarantine. These quarantine experiments, referred to as challenge studies, human infection studies, or "controlled human infection models" involve thousands of clinical samples taken over two to three weeks and can provide a wealth of immunological and molecular data on the infection itself and could allow the discovery of new targets for vaccines and therapeutics. The Yellow Fever studies from 121 years ago gave the impetus for development of a successful vaccine still used today whilst also uncovering the nature of the Yellow Fever agent, namely that it was a virus. We outline how carefully these experiments are approached and the necessity to have high quality units with self-contained air-flow along with extensive personal protective equipment for nursing and medical staff. Most important is the employment of highly trained scientific, medical and nursing staff. We face a future of emerging pathogens driven by the increasing global population, deforestation, climate change, antibiotic resistance and increased global travel. These emerging pathogens may be pathogens we currently are not aware of or have not caused outbreaks historically but could also be mutated forms of known pathogens including viruses such as influenza (H7N9, H5N1 etc.) and coronaviruses. This calls for challenge studies to be part of future pandemic preparedness as an additional tool to assist with the rapid development of broad-spectrum antimicrobials, immunomodulators and new vaccines.
RESUMO
OBJECTIVES: To determine concentrations of matrix metalloproteinase (MMP)-2 and -9 in synovial fluid; and mRNA expression of MMP-1, -13, and -3; interleukin[IL]-1alpha and beta; and tumor necrosis factor (TNF)-alpha in synovial membrane and articular cartilage from horses with naturally occurring joint disease. SAMPLE POPULATION: Synovial fluid (n = 76), synovial membrane (59), and articular cartilage (45) from 5 clinically normal horses and 55 horses with joint disease categorized as traumatic (acute [AT] or chronic [CT]), osteochondritis dissecans (OCD), or septic (S). PROCEDURE: Synovial fluid gelatinase concentrations were analyzed, using zymography. Synovial membrane and articular cartilage mRNA expression for MMP-1, -3, and -13, IL-1alpha and beta, TNF-alpha, type-II collagen, and aggrecan were analyzed, using quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Synovial fluid pro-MMP-2 concentration was significantly higher in diseased joints than normal joints. Septic joints had significantly higher concentrations of pro and active MMP-9. Stromelysin-1 was expressed in > or = 80% of synovial membrane and articular cartilage samples and was strongly influenced by age. Collagenases were rarely expressed, with MMP-13 expressed only in diseased joints. Interleukin-1beta expression was significantly higher in all OCD samples and was influenced by age. Tumor necrosis factor-alpha expression was significantly higher in cartilage from joints with AT and OCD. There was no correlation between MMP or cytokines and type-II collagen or aggrecan expression. CONCLUSIONS AND CLINICAL RELEVANCE: Matrix metalloproteinase-2 and -3 are abundant in naturally occurring joint disease and normal joints. Interleukin-1beta and TNF-alpha may be important in the pathogenesis of OCD. Age affects MMP and IL-1beta concentrations.