Latent tuberculosis testing through the ages: the search for a sleeping killer.

Tuberculosis has been present in the world's population for as long as there has been written language. It is a disease known to the ancient Egyptians, Greeks, Romans, and Hebrews, but its etiology eluded the world for thousands of years. Even after the germ theory was accepted and early scientists hypothesized a pathogen as the cause, the identity of the sleeping killer in society remained a mystery. That is until Robert Koch was able to grow and visualize Mycobacterium tuberculosis. Koch introduced his Old Tuberculin solution as a diagnostic therapy of tuberculosis (TB), with the intent to reduce the number of infected persons and stop its spread. Old Tuberculin's ability to treat TB proved minimal, but its diagnostic potential paved the way for more effective tests from von Pirquet, Calmette, Wolff-Eisner, and Mantoux. Florence Seibert set out to identify and purify the active principle in Koch's Old Tuberculin and ended up creating purified protein derivative (PPD) tuberculin which is still used as the standard for the tuberculin skin test (TST). Interferon-γ release assays (IGRAs) are a more modern diagnostic tool for detecting latent TB infection that offer some benefits (and some disadvantages) to TST. TSTs and IGRAs can determine if an individual has been infected with M. tuberculosis but are equally unable to predict progression to active tuberculosis, the diagnosis of which relies on assessment of clinical symptoms, radiographic imaging, and sample culture.

Augmented KCa2.3 Channel Feedback Regulation of Oxytocin Stimulated Uterine Strips from Nonpregnant Mice.

Uterine contractions prior to 37 weeks gestation can result in preterm labor with significant risk to the infant. Current tocolytic therapies aimed at suppressing premature uterine contractions are largely ineffective and cause serious side effects. Calcium (Ca2+) dependent contractions of uterine smooth muscle are physiologically limited by the opening of membrane potassium (K+) channels. Exploiting such inherent negative feedback mechanisms may offer new strategies to delay labor and reduce risk. Positive modulation of small conductance Ca2+-activated K+ (KCa2.3) channels with cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA), effectively decreases uterine contractions. This study investigates whether the receptor agonist oxytocin might solicit KCa2.3 channel feedback that facilitates CyPPA suppression of uterine contractions. Using isometric force myography, we found that spontaneous phasic contractions of myometrial tissue from nonpregnant mice were suppressed by CyPPA and, in the presence of CyPPA, oxytocin failed to augment contractions. In tissues exposed to oxytocin, depletion of internal Ca2+ stores with cyclopiazonic acid (CPA) impaired CyPPA relaxation, whereas blockade of nonselective cation channels (NSCC) using gadolinium (Gd3+) had no significant effect. Immunofluorescence revealed close proximity of KCa2.3 channels and ER inositol trisphosphate receptors (IP3Rs) within myometrial smooth muscle cells. The findings suggest internal Ca2+ stores play a role in KCa2.3-dependent feedback control of uterine contraction and offer new insights for tocolytic therapies.