Since loss of function
mutations of PINK1 lead to early onset Parkinson’s
disease, there has been growing interest in the discovery of small
molecules that amplify the kinase activity of PINK1. We herein report
the design, synthesis, serum stability, and hydrolysis of four kinetin
riboside ProTides. These ProTides, along with kinetin riboside, activated
PINK1 in cells independent of mitochondrial depolarization. This highlights
the potential of modified nucleosides and their phosphate prodrugs
as treatments for neurodegenerative diseases.
The hydrolysis of BANA by subgingival plaque samples is associated with the presence of either Treponema denticola, Porphyromonas gingivalis, and/or Bacteroides forsythus. A protocol in which pure cultures were incubated for 15 min at 55 degrees C detected about 5 x 10(5) CFU of P. gingivalis and 1 x 10(6) CFU of T. denticola. Clinical studies indicated that the BANA test in this configuration will detect about 10(4) organisms in vivo as compared with the 10(5) to 10(6) organisms found with in vitro grown cells. The BANA test can be made less sensitive by decreasing the time and/or temperature of incubation, which could improve the specificity of the test. In the present study we determined the incubation parameters that would give optimal specificity when the plaque samples were removed from sites of gingival health. Twenty-six approximal plaque samples were taken from each of 90 clinically healthy subjects and incubated with the BANA substrate on PerioScan cards (Oral-B Laboratories) for 5 and 15 min at 35 degrees, 45 degrees, and 55 degrees C. Subjects were randomly assigned to the various temperatures. Wooden toothpicks were inserted interproximally in all sites anterior to distal of the first molars and then each side of the toothpick was wiped onto the PerioScan card. The specificity of the BANA test relative to clinical health was 96% when the cards were incubated for 5 min at 35 degrees C, but decreased to 50-70% when the cards were incubated for 15 min at 35 degrees C or for 5 and 15 min at 45 degrees C and 55 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
A previous multi-center study examining patients diagnosed as having at least four periodontally diseased teeth showed that when (N-Benzoyl-DL-Arginine-Naphthylamide) hydrolysis by periodontal pathogens such as Treponema denticela, Porphyromonas gingivalis, and Bacteroides forsythus was evaluated versus clinical parameters such as clinical judgment of disease, bleeding on probing, and pocket depth, the sensitivity of the test was 84%, 82%, and 87%, respectively, while the specificity was only 42%, 41%, and 32%, respectively. The purpose of the present investigation was to improve the specificity of the test while retaining a high level of sensitivity in both gingivally healthy and periodontally diseased groups. One hundred forty-nine patients participated in this study providing 3,497 interproximal plaque samples. Gingival health was measured using the papillary bleeding score and this was compared with the presence or absence of detectable trypsin-like activity, as determined by the hydrolysis of interproximal plaque samples, using a commercially-available test. Sensitivity and specificity were measured by varying the incubation time and temperature of the enzymatic assay. Using the correlated binomial model to analyze site-specific data within a patient, the specificity was highest at 35°C and 5 minutes incubation (94%), and lowest at 45°C and 15 minutes incubation (33%). Sensitivity was highest at 45°C or 55°C and 15 minutes incubation (90%) and lowest at 35°C and 5 minutes incubation (47%). When the sensitivity and specificity of the test run at 35°C for 5 minutes were used in a model for a diagnostic test proposed by Douglass and Fox, the test has utility when used on older general dental patients and for periodontal patients. / Periodontol 1993; 64:848-852.
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