C uring drug-sensitive tuberculosis (TB) takes 6 to 9 months of combination therapy despite the availability of antibiotics with potent in vitro activity, yet other pulmonary infectious diseases can be cured with single drugs that have similar mechanisms of action with only 3 to 14 days of treatment. One hypothesis used to explain the extended duration required with TB therapy is that subpopulations of bacteria become phenotypically drug tolerant in response to specific local microenvironmental conditions determined by the pathology of individual lesions (37). Understanding the features of these microenvironments and the conditions that generate tolerance may allow a rational design of drug regimens capable of shortening the time required to achieve a durable TB cure, but the methods used to evaluate new regimens have changed little and rely heavily on murine models of tuberculosis that typically have less complex lung pathology than human lesions. Premature discontinuation of treatment in humans results in disease relapse and the presence of cavities, and advanced lung pathology is strongly correlated with relapse (7,19,23). Only the rabbit and nonhuman primate models of pulmonary tuberculosis develop similar heterogeneous pathology, including the formation of cavitary disease. Guinea pigs, and some newer mouse models, develop more highly organized lesions, but these do not progress to cavities (for a comprehensive review of the comparative pathology of tuberculosis animal models, see reference 2).Nonterminal monitoring procedures, such as live imaging modalities, are increasingly being applied during TB drug efficacy experiments in animals and in human clinical trials (12,32,40,52). Structural and/or functional features observed in imaging modalities such as computed tomography (CT) and positron emission tomography (PET) are particularly attractive because they can be measured serially in a single subject at many time points during treatment. Computed tomography (CT) can add highly detailed information to the characteristic features of pulmonary tuberculosis visualized using conventional chest X-rays (1). CT scanning is typically used to monitor patients, assist in diagnosis, and assess surgical options for drug-resistant cases of disease (26), but there have been few examinations of the rate of change in CT findings during chemotherapy. The most detailed study of TB chemotherapy in patients (25) examined high-resolution CT scans from patients undergoing TB chemotherapy for up to 20 months. Old fibrotic lesions could be distinguished from active lesions, and criteria for the state of metabolic activity of lesions were proposed. However, that study did not sequentially

RGS5 is a potent GTPase-activating protein for G i␣ and G q␣ that is expressed strongly in pericytes and is present in vascular smooth muscle cells. To study the role of RGS5 in blood vessel physiology, we generated Rgs5-deficient mice. The Rgs5 ؊/؊ mice developed normally, without obvious defects in cardiovascular development or function. Surprisingly, Rgs5 ؊/؊ mice had persistently low blood pressure, lower in female mice than in male mice, without concomitant cardiac dysfunction, and a lean body habitus. The examination of the major blood vessels revealed that the aortas of Rgs5 ؊/؊ mice were dilated compared to those of control mice, without altered wall thickness. Isolated aortic smooth muscle cells from the Rgs5 ؊/؊ mice exhibited exaggerated levels of phosphorylation of vasodilator-stimulated phosphoprotein and extracellular signal-regulated kinase in response to stimulation with either sodium nitroprusside or sphingosine 1-phosphate. The results of this study, along with those of previous studies demonstrating that RGS5 stability is under the control of nitric oxide via the N-end rule pathway, suggest that RGS5 may balance vascular tone by attenuating vasodilatory signaling in vivo in opposition to RGS2, another RGS (regulator of G protein signaling) family member known to inhibit G protein-coupled receptor-mediated vasoconstrictor signaling. Blocking the function or the expression of RGS5 may provide an alternative approach to treat hypertension.The maintenance of normal blood pressure (BP) is achieved in part by balancing the constriction and dilatation of resistance arterioles via vasoregulatory G protein-coupled receptors (GPCRs). When activated by ligand binding, these GPCRs function as guanine nucleotide exchange factors for heterotrimeric G proteins, triggering downstream effectors and thus producing the biological responses attributed to these receptors. The GTPase activity of G ␣ subunits is subject to control by GTPase-activating proteins (GAPs) called regulators of G protein signaling (RGS) proteins. RGS proteins limit the duration that G ␣ subunits remain GTP bound, thereby negatively regulating GPCR-mediated signaling pathways. Numerous studies with genetically modified animals and with genetic polymorphisms of human populations have underscored the importance of GPCR agonists, GPCRs, and components of GPCR-mediated signaling pathways in BP homeostasis (for a review, see reference 24).A member of the RGS family, RGS2, and GPCR kinase 2 (GRK2), GRK4, and GRK5 have been implicated previously in the regulation of BP. RGS2 is a potent negative regulator of G q␣ , and mice lacking RGS2 are hypertensive due to prolonged signaling by vasoconstrictor GPCR signaling pathways involved in BP control (12). The overexpression of GRK2 or GRK5 in vascular smooth muscle cells (VSMC) also results in a hypertensive phenotype by decreasing GPCR-mediated vasodilation and simultaneously enhancing GPCR-mediated vasoconstriction (8,15). A defective coupling between the dopamine receptor and the G protein-effector ...

Abnormal patterning of coronary arteries (CAs) is a clinically significant problem, and as yet, few animal models have been systematically investigated for coronary patterning defects. Here we characterized coronary artery (CA) insertion and branching patterns of the proximal coronary stems in the hearts of wildtype and heterozygous connexin43 knockout (Cx43␣1 KO) mice. This study entailed the use of high-resolution micro CT imaging for three-dimensional coronary reconstructions. MicroCT of 17 wildtype mice showed a remarkably consistent pattern of CA deployment in the normal mouse heart. Two main CA stems are inserted from the left and right into the aorta. The right coronary artery then branches immediately into the right main and the septal-conal branch, while the left coronary artery branches further distally into the circumflex and the anterior descending CA. This patterning of CA anatomy was confirmed by histology, and by using a vascular smooth muscle or endothelial cell specific lacZ reporter gene to delineate the CAs. A parallel analysis of 25 heterozygous Cx43␣1 KO mouse hearts showed 22 had defects in patterning of the CAs. They exhibited a wide variation in CA anatomy, including abnormal origin and course of the main CA stems, multiple accessories, and dual septal-conal branches. Overall, these studies show loss of one Cx43␣1 allele (haploinsufficiency) leads to a high incidence of coronary patterning defects. These findings suggest CA patterning is sensitive to Cx43␣1 gene dosage.