Pathogenicity of Mycobacterium tuberculosis is closely related to its ability to survive and replicate in the hostile environment of macrophages. For some pathogenic bacteria, secretion of ATP-utilizing enzymes into the extracellular environment aids in pathogen survival via P2Z receptormediated, ATP-induced death of infected macrophages. A component of these enzymes is nucleoside diphosphate kinase (Ndk). The ndk gene was cloned from M. tuberculosis H 37 Rv and expressed in Escherichia coli. Ndk was secreted into the culture medium by M. tuberculosis, as determined by enzymatic activity and Western blotting. Purified Ndk enhanced ATP-induced macrophage cell death, as assayed by the release of [ 14 C]adenine. A catalytic mutant of Ndk failed to enhance ATP-induced macrophage cell death, and periodate-oxidized ATP (oATP), an irreversible inhibitor of P2Z receptor, blocked ATP/Ndk-induced cell death. Purified Ndk was also found to be autophosphorylated with broad specificity for all nucleotides. Conversion of His117fiGln, which is part of the nucleotide-binding site, abolished autophosphorylation. Purified Ndk also showed GTPase activity. Collectively, these results indicate that secreted Ndk of M. tuberculosis acts as a cytotoxic factor for macrophages, which may help in dissemination of the bacilli and evasion of the immune system. Keywords: cytotoxic; Mycobacterium; nucleoside diphosphate kinase; tuberculosis; GTPase.Mycobacterium tuberculosis, the causative agent of tuberculosis, normally replicates in host macrophages. The pathogen has evolved several mechanisms to circumvent the hostile environment of macrophages. These include, (a) inhibition of phagosome-lysosome fusion [1], (b) inhibition of phagosome acidification [2], (c) recruitment and retention of tryptophan/aspartate-containing coat protein on phagosomes to prevent their delivery to lysosomes [3], and (d) expression of members of the host-induced PE-PGRS family of proteins [4]. Another process that occurs with many bacterial pathogens concerns surface-associated P2Z receptors of macrophages. These receptors are involved in the killing of infected macrophages via external ATP that is effluxed from macrophages after activation by the invading pathogen [5]. A component of this system is the bacterial ATP-utilizing enzymes, that are secreted by bacterial pathogens such as, Pseudomonas aeruginosa [6,7], Vibrio cholerae [8], Burkholderia cepacia [9], and from Trichinella spiralis, an intracellular, parasitic nematode [10]. Culture supernatant from P. aeruginosa, V. cholerae, and B. cepacia, harboring Ndk and other ATP-utilizing enzymes, is cytotoxic for macrophages and mast cells when ATP is present at millimolar concentrations [7][8][9]. Ndk is also secreted by the nonpathogenic bacterium M. bovis BCG [11], but addition of culture supernatant of M. bovis BCG prevents ATP-mediated cell death [11]. The culture supernatant of M. bovis BCG also contains an ATPase that can modulate ATP concentrations. As studies on Ndk have been performed using culture supern...
RESULTSOverall, 43 of 60 (72%) women were voiding spontaneously, with a mean postvoid residual volume of 100 mL; 30 (50%) no longer needed to use CISC. During a total of 2878 months of SNS experience, adverse event episodes included lead migration in 20, 'box-site' pain in 19, leg pain/numbness in 18 and loss of response/failure in 18 patients; 53% of the women required a surgical revision related to their implanted stimulator. The efficacy of the two-stage was similar to that of the one-stage procedure (73% vs 70%). Women with a normal urethral sphincter electromyogram had worse outcomes than women with an abnormal test (43% vs 76%). Although the efficacy was no different in those taking analgesia/ antidepressant medication, this group of women had a higher surgical revision rate. Failure and complications for the one-stage procedure were not restricted to the early follow-up period. The mean battery life of the implant was 7.31 years. CONCLUSIONSSNS has sustained long-term efficacy but the procedure has a significant complication rate. At present, the two-stage technique has comparable efficacy to the one-stage technique but a longer-term follow-up is required. The National Institute of Clinical Excellence recommended the use of SNS in women with urinary incontinence who fail to respond adequately to anticholinergic therapy, but patients choosing this treatment should be made aware of the high complication rate associated with the procedure. KEYWORDSsacral neuromodulation, urinary retention, Fowler's syndrome, voiding dysfunction Study Type -Therapy (individual cohort study) Level of Evidence 2b OBJECTIVESTo report our 10-year experience of sacral neurostimulation (SNS) for women in urinary retention, comparing the original one-stage with the newer two-stage technique, as SNS therapy is a well-established treatment for urinary retention secondary to urethral sphincter overactivity (Fowler's syndrome). PATIENTS AND METHODSBetween 1996 and 2006, 60 patients with urinary retention had a SNS device inserted; their case records were reviewed and data on efficacy, follow-up, need for continued clean intermittent self-catheterization (CISC), complications and operative revision rate were assessed.
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