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David Alexander

Publications and source records attributed to David Alexander.

12 recordsLinked to original sources
PubMed2005

Reduced expression of antigenic proteins MPB70 and MPB83 in Mycobacterium bovis BCG strains due to a start codon mutation in sigK.

Mycobacterium bovis Bacille Calmette-Guerin (BCG) strains are genetically and phenotypically heterogeneous. Expression of the antigenic proteins MPB70 and MPB83 is known to vary considerably across BCG strains; however, the reason for this phenotypic difference has remained unknown. By immunoblot, we separated BCG into high- and low-producing strains. By quantitative reverse transcription polymerase chain reaction (RT-PCR), we determined that transcription of the antigen-encoding genes, mpb70 and mpb83, follows the same strain pattern with mRNA levels reduced over 50-fold in low-producing strains. Transcriptome comparison of the same BCG strains by DNA microarray revealed two gene regions consistently downregulated in low-producing strains compared with high-producing strains, one including mpb70 (Rv2875) and mpb83 (Rv2873) and a second that includes the predicted sigma factor, sigK. DNA sequence analysis revealed a point mutation in the start codon of sigK in all low-producing BCG strains. Complementation of a low-producing strain, BCG Pasteur, with wild-type sigK fully restored MPB70 and MPB83 production. Microarray-based analysis and confirmatory RT-PCR of the complemented strains revealed an upregulation in gene transcription limited to the sigK and the mpb83/mpb70 gene regions. These data demonstrate that a mutation of sigK is responsible for decreased expression of MPB70 and MPB83 in low-producing BCG strains and provide clues into the role of Mycobacterium tuberculosis SigK.

Antigens, Bacterial↗
PubMed2004

Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke.

OBJECTIVE: To test the hypothesis that intramuscular (IM) botulinum toxin type A (BTX) reduces excessive muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke. DESIGN: Randomized, double-blind, placebo-controlled, multicenter, 24-week trial. SETTING: Six academic and 13 private US outpatient medical centers. PARTICIPANTS: Ninety-one patients with a mean age of 60 years (range, 30-79 y). Mean time elapsed from ischemic or hemorrhagic stroke to study enrollment was 25.8 months (range, 0.9-226.9 mo). INTERVENTIONS: Up to 2 treatments of placebo, or 90, 180, or 360U of BTX. Concurrent splinting and physical therapy protocols were permitted, but no changes were allowed during the study. MAIN OUTCOME MEASURES: Wrist, elbow, and finger flexor tone assessed by the Modified Ashworth Scale, physician and patient global assessments, pain, FIM instrument, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: Muscle tone decreased more with injections of BTX than with placebo in the wrist flexors at weeks 1, 2, 3, 6, and 9 (P< or =.026); in the elbow flexors at weeks 1, 2, 3, 4, 5, and 9 (P< or =.033); and in the finger flexors at weeks 1 and 3 (P< or =.031). A dose-dependent response was generally observed in tone reduction but not in pain, FIM, or SF-36 measures. CONCLUSIONS: IM BTX reduced muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke but did not appear to affect global quality of life or disability.

Adult↗
PubMed2004

Impact of methoxymycolic acid production by Mycobacterium bovis BCG vaccines.

BCG vaccines are a family of closely related daughter strains of an attenuated isolate of Mycobacterium bovis derived by in vitro passage from 1908 to 1921. During subsequent laboratory propagation of the vaccine strain until its lyophilization in 1961, BCG Pasteur underwent at least seven further genomic mutations. The impact of these mutations on the properties of the vaccine is currently unknown. One mutation, a glycine-to-aspartic acid substitution in the mmaA3 gene, occurred between 1927 and 1931 and impairs methoxymycolic acid synthesis in BCG strains obtained from the Pasteur Institute after this period. Mycolic acids of the cell wall are classified into three functional groups (alpha-, methoxy-, and ketomycolic acids), and together these lipids form a highly specialized permeability barrier around the bacterium. To explore the impact of methoxymycolic acid production by BCG strains, we complemented the functional gene of mmaA3 into BCG Denmark and tested a number of in vitro and in vivo phenotypes. Surprisingly, restoration of methoxymycolic acids alone had no effect on cell wall permeability, resistance to antibiotics, or growth in cultured macrophages and C57BL/6 mice. Our results demonstrate that the loss of methoxymycolic acid production did not apparently affect the virulence of BCG strains.

Amino Acid Substitution↗
PubMed2004

Extensive genomic polymorphism within Mycobacterium avium.

We have initiated comparative genomic analysis of Mycobacterium avium subspecies by DNA microarray, uncovering 14 large sequence polymorphisms (LSPs) comprising over 700 kb that distinguish M. avium subsp. avium from M. avium subsp. paratuberculosis. Genes predicted to encode metabolic pathways were overrepresented in the LSPs, and analysis revealed a polymorphism within the mycobactin biosynthesis operon that potentially explains the in vitro mycobactin dependence of M. avium subsp. paratuberculosis.

Chromosomes, Bacterial↗
PubMed2004

Acquisition of Hrs, an essential component of phagosomal maturation, is impaired by mycobacteria.

Pathogenic mycobacteria survive within macrophages by precluding the fusion of phagosomes with late endosomes or lysosomes. Because the molecular determinants of normal phagolysosome formation are poorly understood, the sites targeted by mycobacteria remain unidentified. We found that Hrs, an adaptor molecule involved in protein sorting, associates with phagosomes prior to their fusion with late endosomes or lysosomes. Recruitment of Hrs required the interaction of its FYVE domain with phagosomal phosphatidylinositol 3-phosphate, but two other attachment sites were additionally involved. Depletion of Hrs by use of small interfering RNA impaired phagosomal maturation, preventing the acquisition of lysobisphosphatidic acid and reducing luminal acidification. As a result, the maturation of phagosomes formed in Hrs-depleted cells was arrested at an early stage, characterized by the acquisition and retention of sorting endosomal markers. This phenotype is strikingly similar to that reported to occur in phagosomes of cells infected by mycobacteria. We therefore tested whether Hrs is recruited to phagosomes containing mycobacteria. Hrs associated readily with phagosomes containing inert particles but poorly with mycobacterial phagosomes. Moreover, Hrs was found more frequently in phagosomes containing avirulent Mycobacterium smegmatis than in phagosomes with the more virulent Mycobacterium marinum. These findings suggest that the inability to recruit Hrs contributes to the arrest of phagosomal maturation induced by pathogenic mycobacteria.

Androstadienes↗
PubMed2003

Botulinum toxin (botox) reduces pain after hemorrhoidectomy: results of a double-blind, randomized study.

PURPOSE: Pain after hemorrhoidectomy appears to be multifactorial and dependent on individual pain tolerance, mode of anesthesia, postoperative analgesia, and surgical technique. Spasm of the internal sphincter is believed to play an important role. The aim of this study was to assess the role of botulinum toxin in reducing pain after Milligan-Morgan hemorrhoidectomy. METHODS: This was a double-blind study of 50 consecutive patients undergoing Milligan-Morgan hemorrhoidectomy and assigned to an internal sphincter injection of 0.4 ml of solution containing either botulinum toxin (20 U; Botox) or normal saline. Patients were managed according to standardized perioperative analgesic and laxative regimens. Pain was assessed by use of daily visual analog scores and analgesia requirements for the first seven postoperative days. RESULTS: Patients randomized to receive botulinum toxin had lower daily average and maximal visual analog scores throughout the study period. The difference reached significance on both Day 6 (P < 0.05) and Day 7 (P < 0.05). There was no significant difference (P = 0.12) in morphine requirements in the first 24 hours (botulinum group, 16 (range, 6-27) mg; placebo arm, 22 (range, 13-41) mg). Patients who received Botox used 19 (range, 8-36) coproxamol tablets in the first seven days after surgery compared with 23 (range, 10-40) in the placebo arm (P = 0.63). CONCLUSIONS: Those patients who had botulinum toxin had significantly less pain toward the end of the first week after surgery. Reduction in spasm within the internal sphincter is the presumed mechanism of action. This is the first reported randomized, controlled trial using botulinum toxin in hemorrhoidectomy.

Botulinum Toxins, Type A↗
PubMed2002

5.2 Ethics, equity and global responsibilities in oral health and disease.

The charge of this Section is ethics and global responsibilities in oral health and disease. Oral health is determined by the same factors as those for general health. To a limited extent, the level of oral health care and dental education. The philosophy and organization of the health care system and dental education, therefore, are key determinants of oral health. Dental education has expanded in many countries where there has been an increase in wealth. Unfortunately, there has been no concomitant increase in the number of dental educators. This is a problem throughout the world. This present situation raises certain ethical issues with regard to professional responsibilities. It also raises some important questions for dental education. This Section has chosen to focus its efforts on examining two issues: * What can be done within dental schools? * What can be done external to dental schools - either individually or collectively? The best practices identified are more akin to goals, as it is recognized that, in a world in which there are enormous variations in economic, environmental, social, and cultural features, a single uniform set of practices is impracticable. The central core value identified is the realization by students, and faculty/teaching staff of the quest of life-long learning against a background of the social and ethical responsibilities of health professionals. The conclusion of the group is that biology is not the sole determinant of health. Understanding the role of social, economic, environmental and other factors in determining health status is critical if greater equity in dental education and care are to be achieved.

Developing Countries↗
PubMed2002

Nature's impartiality, man's inhumanity: reflections on terrorism and world crisis in a context of historical disaster.

This paper compares the terrorist outrages of 11 September 2001 in New York City and Washington to the Lisbon earthquake of 1 November 1755. Both events occurred, literally out of the blue, at critical junctures in history and both struck at the heart of large trading networks. Both affected public attitudes towards disaster as, not only did they cause unparalleled destruction, but they also represented symbolic victories of chaos over order, and of moral catastrophism over a benign view of human endeavour. The Lisbon earthquake led to a protracted debate on teleology, which has some parallels in the debate on technological values in modern society. It remains to be seen whether there will be parallels in the reconstruction and the ways in which major disasters are rationalised in the long term. But despite the differences between these two events--which are obviously very large as nearly 250 years of history separate them and they were the work of different sorts of forces--there are lessons to be learned from the comparison. One of these is that disaster can contribute to a perilous form of self absorption and cultural isolation.

Disasters↗
PubMed2002

Comparison of a nomogram and physician-adjusted dosage of warfarin for prophylaxis against deep-vein thrombosis after arthroplasty.

BACKGROUND: Warfarin is an effective agent for prophylaxis against deep-vein thrombosis following total hip or knee arthroplasty. However, management with warfarin in the postoperative setting is problematic because of the need for anticoagulant monitoring. We developed a nomogram for the dosing of warfarin that was specific for joint arthroplasty. The objective of this study was to compare the performance of this nomogram with that of physician-adjusted dosing of warfarin for patients undergoing total hip or knee arthroplasty. METHODS: The study involved two cohort trials. The historical control group consisted of 1024 patients who underwent total hip or knee arthroplasty during the course of a clinical trial (the Post-Arthroplasty Screening Study [PASS]) in which all warfarin dose adjustments were made by two hematologists. The first dose of warfarin was given on the evening of the surgery, and the warfarin dose was adjusted daily on the basis of the international normalized ratio and was discontinued at the time of discharge from the hospital. In the PASS study, the dosage of warfarin was designed to prolong the international normalized ratio to 1.7 by postoperative day 4 and to maintain it between 1.8 and 2.5 until discharge from the hospital. Subsequently, a warfarin nomogram was developed on the basis of the dose adjustments used in the PASS study, and it was used prospectively to manage a cohort of 729 patients undergoing total hip or knee arthroplasty. In the nomogram cohort, the initial dose of warfarin was given on the evening of the surgery. Both cohorts were followed for twelve weeks after the surgery to determine if any venous thromboembolic complications had developed. RESULTS: The nomogram cohort and the control cohort had similar daily doses of warfarin (mean, 3.2 versus 3.3 mg) and levels of international normalized ratio on postoperative day 4 (mean, 1.9 versus 1.9) (p > 0.2). The average number of days to achieve an international normalized ratio of >1.7 was 4.0 for the nomogram cohort compared with 4.3 for the control cohort (p = 0.01). The percentage of days that the international normalized ratio was between 1.8 and 2.5 was 61% for the nomogram cohort and 58% for the control cohort (p < 0.01), and the percentage of days that the international normalized ratio was >3.0 was only 6.5% for the nomogram cohort and 6.0% for the control cohort (p > 0.2). Eighty-two percent of the patients managed with the nomogram achieved an international normalized ratio of >1.7 by the time of discharge from the hospital compared with 92% in the control cohort (p = 0.01). In the three-month follow-up period, a deep-vein thrombosis or a nonfatal pulmonary embolism developed in nineteen patients (2.6%; 95% confidence interval, 1.6% to 4.0%) in the nomogram cohort compared with fourteen patients (1.4%; 95% confidence interval, 0.7% to 2.3%) in the control cohort. No major bleeding event or fatal pulmonary embolism was observed in the patients managed with use of the nomogram. CONCLUSION: This study demonstrated that the administration of warfarin during hospitalization with use of a nomogram designed for the prevention of deep-vein thrombosis following total hip or knee arthroplasty provided effective and safe prophylaxis that was comparable with that provided by physician-adjusted dosing of warfarin.

Anticoagulants↗
PubMedDate not supplied

Terrorism, disasters, and security.

The purpose of this editorial is to explore the relationship between the new global emphasis on terrorism and the developing academic and practical fields of disaster management. It includes an appraisal of the place of terrorism among the various forms of disaster, a consideration of its relationship to risk assessment and its place in the practical handling of risks and incidents, and some reflections on the role of the private sector in security management. The influence on the current attitude toward managing the terrorism threat by the evolution of the disaster management field is considered and some of the problems with defining scenarios for counter-terrorism planning also are discussed.

Disaster Planning↗