In reality, the use of the anti-psychotic phenothiazine, thioridazine for therapy of multidrug and extensively drugresistant tuberculosis infections is now getting seriously thought of

h after infectious diseases in low- and middle-income countries [2]. In those surviving the immediate lethal injury, the most important cause of death is hypovolemic circulatory collapse (HCC) [3]. The proposed mechanisms for development of HCC are cardiac dysfunction, abnormalities in vascular tone and capillary leak [4,5]. Better delineation of the specific contributions of each of these abnormalities to HCC and an understanding of the molecular and cellular mechanisms underlying each abnormality has the potential to yield new strategies to prevent HCC. To gain new mechanistic insights and to develop resuscitation strategies that prevent HCC, we developed a protocol in rats of minor trauma plus severe HS that reproducibly results in HCC. HCC in our model involves cardiac dysfunction secondary to cardiomyocyte apoptosis. IL-6 All four strains, had been either treated with Damage to Mtb cell-envelope by THZ Modulation of intracellular redox potential by THZ Earlier research administration at the start of resuscitation prevents HCC, reverses cardiac dysfunction, improves mortality and eliminates cardiomyocyte apoptosis, at least in part, through activation of Stat3 which acts to normalize the shock induced apoptosis pathway transcriptome. These findings support further investigation of IL-6, or other Stat3 activators, as an adjuvant for resuscitation of trauma patients with severe HS to prevent HCC.These studies were approved by the Baylor College of Medicine Institutional Review Board for animal experimentation and conform to National Institutes of Health guidelines for the care and use of laboratory animals. Adult male Sprague-Dawley rats were obtained from Harlan (Indianapolis, IN). Stat3b homozygous-deficient (Stat3bD/D) mice were generated as described [6] and re-derived at Jackson labs. Pups from heterozygous matings were tailed and genotyped by PCR, as described, with minor modifications [6]. Rats (25050 gm) were acclimatized and subjected to the sham or hemorrhagic shock (HS) protocols, as described [7,8] with modifications. Blood (22.5 ml/kg body weight) was withdrawn into a heparinized syringe over 10 min then episodically thereafter to maintain the target MAP at 35 mmHg until blood pressure compensation failed. Blood was then returned as needed to maintain the target MAP. The amount of shed blood returned (SBR) defined 5 different levels of shock severity reflected in the duration of hypotension: 0% SBR (SBR0) represented the lowest level of shock severity (duration of hypotension, 7862.5 minutes), 10% SBR (SBR10; duration of hypotension, 149641.4 minutes), 20% SBR (SBR20; duration of hypotension, 165632.7 minutes), 35% SBR (SBR35; duration of hypotension, 21167.6 minutes), and 50% SBR (SBR50; duration of hypotension, 273624.9 minutes). At the end of the hypotensive period, rats were fluid resuscitated over 30 min as described [7,8]. Fluid resuscitation consisted of return of the remaining shed blood followed by a volume of Ringer's solution equal to 2 times the total shed blood volume. Ringer's solution contained a racemic mixture of L- and D-lactate. The MAP was observed at the end of resuscitation to assess for hypovolemic circulatory collapse (HCC) then the rats were humanely sacrificed 60 minutes after the start of resuscitation. HCC was defined as failing to achieve a MAP at the end of fluid resuscitation within the normal range of rats examined i.e. 72 mm Hg [the mean (94 mm Hg) minus two SD (11 mm Hg) of starting BP]. Where indicated, rats received 10 mg/kg of recombinant human IL-6 in 0.1 ml phosphate-buffered saline (PBS, pH 7.4) at the initiation of resuscitation