c Mycobacterium tuberculosis persists in the tissues of mammalian hosts despite inducing a robust immune response dominated by the macrophage-activating cytokine gamma interferon (IFN-␥). We identified the M. tuberculosis phosphate-specific transport (Pst) system component PstA1 as a factor required to resist IFN-␥-dependent immunity. A ⌬pstA1 mutant was fully virulent in IFN-␥ ؊/؊ mice but attenuated in wild-type (WT) mice and mice lacking specific IFN-␥-inducible immune mechanisms: nitric oxide synthase (NOS2), phagosome-associated p47 GTPase (Irgm1), or phagocyte oxidase (phox). These phenotypes suggest that ⌬pstA1 bacteria are sensitized to an IFN-␥-dependent immune mechanism(s) other than NOS2, Irgm1, or phox. In other species, the Pst system has a secondary role as a negative regulator of phosphate starvation-responsive gene expression through an interaction with a two-component signal transduction system. In M. tuberculosis, we found that ⌬pstA1 bacteria exhibited dysregulated gene expression during growth in phosphate-rich medium that was mediated by the two-component sensor kinase/response regulator system SenX3-RegX3. Remarkably, deletion of the regX3 gene suppressed the replication and virulence defects of ⌬pstA1 bacteria in NOS2 ؊/؊ mice, suggesting that M. tuberculosis requires the Pst system to negatively regulate activity of RegX3 in response to available phosphate in vivo. We therefore speculate that inorganic phosphate is readily available during replication in the lung and is an important signal controlling M. tuberculosis gene expression via the Pst-SenX3-RegX3 signal transduction system. Inability to sense this environmental signal, due to Pst deficiency, results in dysregulation of gene expression and sensitization of the bacteria to the host immune response.

BackgroundThe use of peripheral nerve blocks for anesthesia and postoperative analgesia has increased significantly in recent years. Adjuvants are frequently added to local anesthetics to prolong analgesia following peripheral nerve blockade. Numerous randomized controlled trials and meta-analyses have examined the pros and cons of the use of various individual adjuvants.ObjectivesTo systematically review adjuvant-related randomized controlled trials and meta-analyses and provide clinical recommendations for the use of adjuvants in peripheral nerve blocks.MethodsRandomized controlled trials and meta-analyses that were published between 1990 and 2014 were included in the initial bibliographic search, which was conducted using Medline/PubMed, Cochrane Central Register of Controlled Trials, and EMBASE. Only studies that were published in English and listed block analgesic duration as an outcome were included. Trials that had already been published in the identified meta-analyses and included adjuvants not in widespread use and published without an Investigational New Drug application or equivalent status were excluded.ResultsSixty one novel clinical trials and meta-analyses were identified and included in this review. The clinical trials reported analgesic duration data for the following adjuvants: buprenorphine (6), morphine (6), fentanyl (10), epinephrine (3), clonidine (7), dexmedetomidine (7), dexamethasone (7), tramadol (8), and magnesium (4). Studies of perineural buprenorphine, clonidine, dexamethasone, dexmedetomidine, and magnesium most consistently demonstrated prolongation of peripheral nerve blocks.ConclusionsBuprenorphine, clonidine, dexamethasone, magnesium, and dexmedetomidine are promising agents for use in prolongation of local anesthetic peripheral nerve blocks, and further studies of safety and efficacy are merited. However, caution is recommended with use of any perineural adjuvant, as none have Food and Drug Administration approval, and concerns for side effects and potential toxicity persist.

There is an epidemic of opioid use, abuse, and misuse in the United States, which results in significant morbidity and mortality. It may be difficult to reduce perioperative opioid use given known acute surgical trauma and resultant pain; however, the discrete and often limited nature of postoperative pain also may make management easier in part by utilizing nonopioid modalities, such as regional anesthesia/analgesia, and multimodal analgesia, which may decrease the need for powerful opioids. This article reviews the relevant literature describing the use of adjunct medications, regional anesthesia and analgesic techniques, and regional block additives in the context of providing adequate pain control while lessening opioid use.

Onset of the adaptive immune response in mice infected with Mycobacterium tuberculosis is accompanied by slowing of bacterial replication and establishment of a chronic infection. Stabilization of bacterial numbers during the chronic phase of infection is dependent on the activity of the gamma interferon (IFN-␥)-inducible nitric oxide synthase (NOS2). Previously, we described a differential signature-tagged mutagenesis screen designed to identify M. tuberculosis "counterimmune" mechanisms and reported the isolation of three mutants in the H37Rv strain background containing transposon insertions in the rv0072, rv0405, and rv2958c genes. These mutants were impaired for replication and virulence in NOS2 ؊/؊ mice but were growth-proficient and virulent in IFN-␥ ؊/؊ mice, suggesting that the disrupted genes were required for bacterial resistance to an IFN-␥-dependent immune mechanism other than NOS2. Here, we report that the attenuation of these strains is attributable to an underlying transposon-independent deficiency in biosynthesis of phthiocerol dimycocerosate (PDIM), a cell wall lipid that is required for full virulence in mice. We performed whole-genome resequencing of a PDIM-deficient clone and identified a spontaneous point mutation in the putative polyketide synthase PpsD that results in a G44C amino acid substitution. We demonstrate by complementation with the wild-type ppsD gene and reversion of the ppsD gene to the wild-type sequence that the ppsD(G44C) point mutation is responsible for PDIM deficiency, virulence attenuation in NOS2 ؊/؊ and wild-type C57BL/6 mice, and a growth advantage in vitro in liquid culture. We conclude that PDIM biosynthesis is required for M. tuberculosis resistance to an IFN-␥-mediated immune response that is independent of NOS2.Pathogenic mycobacteria possess a unique array of complex cell wall-associated lipids. The most abundant of these lipids, the phthiocerol dimycocerosates (PDIMs) (Fig. 1), are among the best characterized (23). PDIMs contain long-chain diols esterified by methyl-branched fatty acid chains. As early as 1974, it was recognized that a spontaneously arising PDIMdeficient variant of the laboratory strain H37Rv was attenuated in a guinea pig model of infection (11). Shortly thereafter, it was shown that the in vivo survival of an avirulent Mycobacterium tuberculosis strain was enhanced by coating the bacteria with cholesterol oleate and purified PDIM (16). A genetic link between PDIM production and virulence was not established until a quarter century later, when a large chromosomal locus was identified as playing an essential role in the biosynthesis and export of PDIM (3,4,6). Transposon insertions within the fadD26, fadD28, mmpL7, and drrC genes, and in the putative transcriptional promoter region upstream of the fadD26 gene, were identified in strains deficient in surface-localized PDIM. The fadD26 and fadD28 mutants apparently fail to synthesize PDIM, whereas the mmpL7 and drrC mutants produce PDIM but accumulate it intracellularly, thus implicating these ...

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Between 1998 and 2008, trends show increases in several major in-hospital complications after THA and TKA, including pulmonary embolism, sepsis, nonmyocardial infarction cardiac complications, and pneumonia. Despite the increase in complications, declining in-hospital mortality was noted over this period.

Study Design Analysis of the National Inpatient Sample database from 2000 to 2008. Objective To identify if metabolic syndrome is an independent risk factor for increased major perioperative complications, cost, length of stay and non-routine discharge. Summary of Background Data Metabolic syndrome is a combination of medical disorders that has been shown to increase the health risk of the general population. No study has analyzed its impact in the perioperative spine surgery setting. Methods We obtained the National Inpatient Sample from the Hospital Cost and Utilization Project for each year between 2000 and 2008. All patients undergoing primary posterior lumbar spine fusion were identified and separated into groups with and without metabolic syndrome. Patient demographics and health care system related parameters were compared. The outcomes of major complications, non-routine discharge, length of hospital stay and hospitalization charges were assessed for both groups. Regression analysis was performed to identify if the presence of metabolic syndrome was an independent risk factor for each outcome. Results An estimated 1,152,747 primary posterior lumbar spine fusion were performed between 2000 and 2008 in the US. The prevalence of metabolic syndrome as well as the comorbidities of the patients increased significantly over time. Patients with metabolic syndrome had significantly longer length of stay, higher hospital charges, higher rates of non-routine discharges and increased rates of major life-threatening complications compared to patients without metabolic syndrome. Conclusion Patients with metabolic syndrome undergoing primary posterior lumbar spinal fusion represent an increasing financial burden on the health care system. Clinicians should recognize that metabolic syndrome represents a risk factor for increased perioperative morbidity.

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