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Biomedical subjects

D B Young

Publications and source records attributed to D B Young.

At least 19 recordsLinked to original sources
PubMed2006

Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients.

OBJECTIVE: To determine the extent of pyrazinamide (PZA) resistance in isolates from previously treated patients from the Western Cape, South Africa. DESIGN: Drug-resistant isolates, isolates resistant to one or more drugs other than PZA (PZA resistance is not routinely determined) (n = 127), and drug-susceptible (n = 47) clinical isolates of Mycobacterium tuberculosis from previously treated patients from the Western Cape were phenotypically (BACTEC MGIT 960) and genotypically (pncA gene sequencing) analysed for PZA resistance. RESULTS: MGIT analysis found that 68 of the 127 drug-resistant isolates were PZA-resistant. Nearly all (63/68) PZA-resistant isolates had diverse nucleotide changes scattered throughout the pncA gene, and five PZA-resistant isolates had no pncA mutations. Of the 47 phenotypically susceptible isolates, 46 were susceptible to PZA, while one isolate was PZA-monoresistant (OR = 53.0, 95% CI = 7.1-396.5). A pncA polymorphism (Thr114Met) that did not confer PZA resistance was also identified. PZA resistance was strongly associated with multidrug-resistant tuberculosis (MDR-TB). CONCLUSION: An alarmingly high proportion of South African drug-resistant M. tuberculosis isolates are PZA-resistant, indicating that PZA should not be relied upon in managing patients with MDR-TB in the Western Cape. A method for the rapid detection of PZA resistance would be beneficial in managing patients with suspected drug resistance.

Antitubercular Agents↗
PubMed2004

Lower limb landmine injuries.

The medical records of 186 patients seeking treatment for landmine injuries in the authors' region between 1993 and 2001 were evaluated. Of these patients 13 died of accompanying complications. Ten (10) patients with general body trauma and upper limb trauma were excluded from the study. Of 163 patients with lower-limb injuries included in the study, 21 with traumatic amputation underwent surgical amputation at different levels. Patients without traumatic amputation were divided into 2 groups. There were 41 patients (29%) in Group I who were treated by limb salvage procedures. Treatments used in Group I including wound debridement, tendon repair, skin approximation, minimal osteosynthesis, external fixation of long bones and secondary wound coverage. In Group II, there were 101 patients (71%) with primary amputation. Trans-tibial amputation was performed in 52 cases (51.4%), ankle disarticulation in 24 (23.7%), trans-femoral amputation in 9 (8.9%), partial foot amputation in 8 (7.9%), knee disarticulation in 7 (6.9%) and hip disarticulation in 1 case. In Group I, there was infection in 21 patients (51.2%), revision in 27 (65.8%), and amputation in 15 (36.5%). In Group II, there was infection in 28 patients (27.7%), revision in 17 (16.8%), and amputation at a higher level in 8 (7%). In crush injuries such as those resulting from landmines, soft tissue, vascular, and neurological assessment must be performed with utmost care. Even so, the desired success in interventions intended to save a limb is complicated by a high infection rate, soft tissue complications, and high revision amputation rates. Therefore, a decision to amputate in the early term based on an accurate preoperative assessment is crucial.

Adolescent↗
PubMed2003

The effect of mycobacterial virulence and viability on MAP kinase signalling and TNF alpha production by human monocytes.

SETTING: The success of Mycobacterium tuberculosis as a human pathogen depends on its ability to tolerate and perhaps manipulate host defense mechanisms. OBJECTIVE: To determine the induction of tumour necrosis factor-alpha (TNF alpha), a central mediator of immunity, by human monocytes infected with virulent M. tuberculosis, M. leprae and attenuated M. bovis BCG. DESIGN: Mycobacteria-induced cellular activation pathways of TNF alpha production was investigated using an inhibitor of protein tyrosine kinase (PTKs) and an inhibitor of mitogen-activated protein (MAP) kinases. RESULTS: TNF alpha production was significantly lower during infection with virulent M. tuberculosis than with BCG and this differential response was independent of mycobacterial viability. TNF alpha production involved the PTK and MAP kinase pathways. Reduced TNF alpha induction by M. tuberculosis was associated with a reduction in the extent and duration of phosphorylation of extracellular-signal regulated kinases (ERK 1/2). Infection with M. leprae triggered low and transient ERK 1/2 activation as well as low TNF alpha production. CONCLUSION: Maintenance of the differential response in both live and heat-killed preparations suggests that the reduced TNF alpha response associated with virulent mycobacteria is due to differences in the presence of components capable of triggering host pattern recognition receptors, rather than events associated with phagosome trafficking or the active release of intracellular modulators.

BCG Vaccine↗
PubMed2003

Koch's bacillus - a look at the first isolate of Mycobacterium tuberculosis from a modern perspective.

Using molecular methods the authors have studied mycobacterial DNA taken from a 19th century victim of tuberculosis. This was the case from which Robert Koch first isolated and cultured the organism responsible for tuberculosis. The mycobacteria were preserved within five glass culture tubes as abundant bacterial colonies on slopes of a gelatinous culture medium of unknown composition. Originally presented by Koch to surgical laryngologist Walter Jobson Horne in London in 1901, the relic has, since 1983, been in the care of the Royal College of Surgeons of England. Light and electron microscopy established the presence of acid-fast mycobacteria but showed that morphological preservation was generally poor. Eleven different genomic loci were successfully amplified by PCR. This series of experiments confirmed that the organisms were indeed Mycobacterium tuberculosis and further showed that the original strain was in evolutionary terms similar to 'modern' isolates, having undergone the TB D1 deletion. Attempts to determine the genotypic group of the isolate were only partially successful, due in part to the degraded nature of the DNA and possibly also to a truncation in the katG gene, which formed part of the classification scheme. Spoligotyping resulted in amplification of DR spacers consistent with M. tuberculosis but with discrepancies between independent extracts, stressing the limitations of this typing method when applied to poorly preserved material.

Bacteriology↗
PubMed2001

Is there stereoelectronic control in hydrolysis of cyclic guanidinium ions?

To assess stereoelectronic effects in the cleavage of tetrahedral intermediates, a series of five-, six-, and seven-membered cyclic guanidinium salts was synthesized. If stereoelectronic control by antiperiplanar lone pairs is operative, these are expected to hydrolyze with endocyclic C-N cleavage to acyclic ureas. However, hydrolysis in basic media produces mixtures of cyclic and acyclic products, as determined by 1H NMR analysis. The results show that in the six-membered ring antiperiplanar lone pairs provide a weak acceleration of the breakdown of the tetrahedral intermediate, but in five- and seven-membered rings there is no evidence for such acceleration, which instead can be provided by syn lone pairs.

Guanidine↗
PubMed2001

Stereoelectronic control in addition of nucleophiles to an amidinium ion.

Nucleophilic addition to 1,3-dimethyl-5-phenyl-1,4,5,6-tetrahydropyrimidinium ion provides a quantitative measure of stereoelectronic control. This amidinium ion presents the nucleophile with two distinct paths for attack. Axial attack is favored by interaction between the orbital of the developing bond and antiperiplanar lone pairs on the nitrogens. Reaction of the amidinium salt with diverse nucleophiles (D(-), H3C(-), n-Bu(-), PhCH2(-), allyl(-), Ph(-), C5F6(-), CH2=CH(-), HC triple bond C(-), PhC triple bond C(-), CN(-)) produces mixtures of cis and trans stereoisomers. Both kinetic and thermodynamic product distributions were measured by 1H NMR, before and after acid-catalyzed equilibration. The values provide insight into the roles of steric and stereoelectronic forces at the transition state and in products. Stereoelectronic effects on reactivity are found to be weak (ca. 1 kcal/mol).

Amides↗
PubMed2001

Contribution of Th1 and Th2 cells to protection and pathology in experimental models of granulomatous lung disease.

Mice that had received adoptive transfer of DO11.10 TCR transgenic T cells polarized toward a Th1 or a Th2 phenotype were challenged with Ag-coated beads or with recombinant Mycobacterium tuberculosis expressing the OVA determinant. The resulting bead-induced pulmonary granulomas reflected the phenotype of the adoptively transferred T cells, with the Th2 cells promoting a fibrotic reaction. Mice receiving Th1 cells mounted an epitope-specific protective response to challenge with recombinant M. tuberculosis. Th2 recipients were characterized by enhanced weight loss and lung fibrosis during acute high-dose infection. The combination of TCR transgenic T cells and epitope-tagged mycobacteria provides a novel experimental model for investigation of the pathogenesis of tuberculosis.

Adoptive Transfer↗
PubMed2001

Paleopathological and biomolecular study of tuberculosis in a medieval skeletal collection from England.

Nine human skeletons of medieval date from a rural English burial site show signs of skeletal tuberculosis. They were subject to polymerase chain reaction (PCR) assays aimed at detecting traces of DNA from infecting mycobacteria, with the purpose both of confirming the paleopathological diagnosis of tuberculosis and determining in individual cases whether disease was due to M. tuberculosis or M. bovis. In all nine cases, evidence for M. tuberculosis complex DNA was found, and in all instances it appeared that disease was due to M. tuberculosis rather than M. bovis. The significance of the findings for understanding tuberculous infection in rural agrarian communities in medieval England is discussed.

Adult↗
PubMed2001

Elevated potassium intake inhibits neointimal proliferation in the swine coronary artery.

BACKGROUND: Previously, we reported that elevated extracellular potassium concentration in vitro inhibited proliferation and migration of vascular smooth muscle cells, formation of free radical compounds by macrophages, and reduced platelet sensitivity to agonists. More recently, we described a reduction in neointimal proliferation after balloon angioplasty injury in the carotid arteries of rats associated with an elevation of dietary potassium intake during a 4-week experiment. In the present study we conducted a similar investigation in the swine coronary artery balloon angioplasty model. PROCEDURES: Two groups of seven castrated male swine were studied; for 28 days the normal potassium group consumed a diet containing 0.25% potassium and the high potassium group ate diet containing 2.0% potassium. After 14 days on the diet, balloon angioplasty was performed. After an additional 14 days on the same diets the hearts were removed, and normal and lesioned sections of the artery were analyzed histologically. RESULTS: The neointimal area was markedly less in the high potassium group than in the normal potassium group, 0.33+/-0.04 mm2 v 0.74+/-0.10 mm2 (P < .004). Neointimal area-to-total wall area ratio in the normal potassium group averaged 0.199+/-0.018, significantly greater than the ratio computed for the elevated potassium group, 0.120+/-0.015 (P < .006). CONCLUSION: These results support the hypothesis that a high level of dietary potassium intake inhibits neointimal proliferation after balloon angioplasty in the swine coronary artery.

Aldosterone↗
PubMed2001

Leprosy lipid provides the key to Schwann cell entry.

A recent study has demonstrated that the species-specific phenolic glycolipid of Mycobacterium leprae triggers uptake into Schwann cells by interaction with laminin-2 and the alpha-dystroglycan receptor. This finding emphasizes the importance of lipids in the biology of mycobacterial infection and suggests possible strategies to combat nerve damage in leprosy.

Animals↗
PubMed2001

A post-genomic perspective.

The complete genome sequence of Mycobacterium tuberculosis, along with novel genetic tools, provides the foundation for a new era of post-genomic research. The challenge is now to translate these opportunities into an improved understanding of the complex biology of tuberculosis infection.

Carrier State↗
PubMed2001

Overexpression of heat-shock proteins reduces survival of Mycobacterium tuberculosis in the chronic phase of infection.

Elevated expression of heat-shock proteins (HSPs) can benefit a microbial pathogen struggling to penetrate host defenses during infection, but at the same time might provide a crucial signal alerting the host immune system to its presence. To determine which of these effects predominate, we constructed a mutant strain of Mycobacterium tuberculosis that constitutively overexpresses Hsp70 proteins. Although the mutant was fully virulent in the initial stage of infection, it was significantly impaired in its ability to persist during the subsequent chronic phase. Induction of microbial genes encoding HSPs might provide a novel strategy to boost the immune response of individuals with latent tuberculosis infection.

Animals↗
PubMed2001

Analysis of recombinant mycobacteria as T helper type 1 vaccines in an allergy challenge model.

The potential for development of mycobacteria as T helper type 1 (Th1) vaccines capable of induction of Th1 responses to recombinant antigens was explored in a model system based on an immunodominant peptide from house dust mite. Different recombinant mycobacterial preparations were compared for their ability to induce a Th1 response to the peptidea. It was found that mycobacterial viability was not a prerequisite for Th1 immunogenicity. A dominant interferon-gamma (IFN-gamma) response to peptide was observed in splenocytes from C57BL/6J mice immunized with live or heat-killed preparations of recombinant Mycobacterium vaccae or with live attenuated bacillus Calmette-Guèrin (BCG) vaccine expressing the antigen. Interleukin-5 (IL-5), a marker of a Th2 response, was detected only in mice receiving live M. vaccae. A similar pattern was observed in BALB/b mice, although the magnitude of the IFN-gamma response was much lower. Control and immunized mice were subsequently exposed to allergen using a Th2-inducing challenge protocol. A significant shift from a Th2 to a Th1 response was observed in immunized mice, as judged by cytokine expression by splenocytes and by subclass of circulating antibody. The effect was seen in three inbred mouse strains differing in their innate bias towards Th1 or Th2 responses. It was dependent on the presence of specific antigen in the mycobacterial preparation and, under the immunization conditions tested, was more pronounced with dead M. vaccae than with live BCG as carrier vaccine. The results demonstrate the potency of killed mycobacteria as Th1 adjuvants and suggest a potential application for recombinant mycobacteria in antigen-specific immune modulation.

Adjuvants, Immunologic↗
PubMed2001

Investigation and control of a large outbreak of multi-drug resistant tuberculosis at a central Lisbon hospital.

An increase in the number of new cases of tuberculosis (TB) combined with poor clinical outcome was identified among HIV-infected injecting drug users attending a large HIV unit in central Lisbon. A retrospective epidemiological and laboratory study was conducted to review all newly diagnosed cases of TB from 1995 to 1996 in the HIV unit. Results showed that from 1995 to 1996, 63% (109/173) of the Mycobacterium tuberculosis isolates from HIV-infected patients were resistant to one or more anti-tuberculosis drugs; 89% (95) of these were multidrug-resistant, i.e., resistant to at least isoniazid and rifampicin. Eighty percent of the multidrug-resistant strains (MDR) available for restriction fragment length polymorphism (RFLP) DNA fingerprinting clustered into one of two large clusters. Epidemiological data support the conclusion that the transmission of MDR-TB occurred among HIV-infected injecting drug users exposed to infectious TB cases on open wards in the HIV unit. Improved infection control measures on the HIV unit and the use of empirical therapy with six drugs once patients were suspected to have TB, reduced the incidence of MDR-TB from 42% of TB cases in 1996 to 11% in 1999.

AIDS-Related Opportunistic Infections↗
PubMed2001

Novel strategies for intervention targeted at mycobacterial persistence.

Effective global control of tuberculosis is likely to require intervention at multiple points in the course of infection. In addition to existing approaches based on treatment of active disease and preventive vaccination of unexposed individuals, current research on the biology of mycobacterial persistence suggests the potential for the development of novel disease-control strategies targeted at infected asymptomatic populations.

Animals↗