Over-expression of cyclo-oxygenase-2 predicts poor survival of patients with nasopharyngeal carcinoma: a meta-analysis.

OBJECTIVES: The conclusive prognostic significance of cyclo-oxygenase-2 has been determined in various cancers but not in nasopharyngeal carcinoma. Therefore, this study aimed to evaluate the relationship of cyclo-oxygenase-2 expression with the survival outcome and treatment response of nasopharyngeal carcinoma patients via a systematic meta-analysis approach. METHODS: A meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses ('PRISMA') checklist. The primary clinical characteristics of patients, and hazard ratios with 95 per cent confidence intervals of overall survival data, were tabulated from eligible studies. The relationship of cyclo-oxygenase-2 expression with survival outcome (expressed as hazard ratio) and treatment response (expressed as odds ratio) in nasopharyngeal carcinoma patients was analysed, and explained with the aid of forest plot charts. RESULTS AND CONCLUSION: The pooled hazard ratio for overall survival was 2.02 (95 per cent confidence interval = 1.65-2.47). This indicates that the over-expression of cyclo-oxygenase-2 is significantly associated with the poor survival of nasopharyngeal carcinoma patients. The pooled odds ratio of 0.98 (95 per cent confidence interval = 0.27-3.49) reveals that over-expression of cyclo-oxygenase-2 was not significantly related to the treatment outcome.

Self-Assembled Silica Nanostructures: Simultaneous Discrimination of Handedness, Pitch and Diameter of Helical Silica Nanotubes.

The left- and right-handed helical silica nanostructures were obtained with the aid of organic templates, the formation of the nanostructures might follow a co-operation self-assembly mechanism. The chirality of the organogel self-assemblies was successfully transcribed in to the silica. The helical pitch and pore size of the silica nanotubes sensitively depended on the optical purity of the neutral gelator in the reaction mixtures.

Obesity leads to declines in motor skills across childhood.

BACKGROUND: Poor motor skills have been consistently linked with a higher body weight in childhood, but the causal direction of this association is not fully understood. This study investigated the temporal ordering between children's motor skills and weight status at 5 and 10 years. METHODS: Participants were 668 children (54% male) who were studied from infancy as part of an iron deficiency anaemia preventive trial and follow-up study in Santiago, Chile. All were healthy, full-term and weighing 3 kg or more at birth. Cross-lagged panel modelling was conducted to understand the temporal precedence between children's weight status and motor proficiency. Analyses also examined differences in gross and fine motor skills among healthy weight, overweight, and obese children. RESULTS: A higher BMI at 5 years contributed to declines in motor proficiency from 5 to 10 years. There was no support for the reverse, that is, poor motor skills at 5 years did not predict increases in relative weight from 5 to 10 years. Obesity at 5 years also predicted declines in motor proficiency. When compared with normal weight children, obese children had significantly poorer total and gross motor skills at both 5 and 10 years. Overweight children had poorer total and gross motor skills at 10 years only. The differences in total and gross motor skills among normal weight, overweight and obese children appear to increase with age. There were small differences in fine motor skill between obese and non-obese children at 5 years only. CONCLUSIONS: Obesity preceded declines in motor skills and not the reverse. Study findings suggest that early childhood obesity intervention efforts might help prevent declines in motor proficiency that, in turn, may positively impact children's physical activity and overall fitness levels.

Multivariate assessment of site of lingual nerve.

Injury to the lingual nerve can cause debilitating symptoms. The nerve lies in the retromolar region and its anatomical site can vary within patients and according to sex, age, and dentate status. To our knowledge, no previous studies have recorded its course from multiple bony landmarks and examined the association between age, dentate status, and sex, in the same sample. We dissected 30 white cadavers and took primary and secondary reference points from the internal oblique ridge. We measured the distance to the lingual nerve in sagittal, vertical, and horizontal planes, and recorded the position where the nerve was closest to the lingual plate. We dissected 46 hemimandibles (23 male, mean age 79 years, range 52-100) of which 26 were from the left side. Mean (SD) sagittal, vertical, and horizontal distances from the primary reference point were 9.29 (3.41)mm, 9.15 (3.87)mm, and 0.57 (0.56)mm, respectively. Mean (SD) vertical and horizontal distances from the secondary point were 7.79 (5.45) mm and 0.59 (0.64)mm, respectively. The proximity of the nerve to the lingual plate varied widely (range -13.00 to 15.17mm from the primary reference point). Dentate status was significant for the sagittal measurement from the primary point, and the vertical measurement from the secondary point. Differences in age, sex, or site of the contralateral nerve were not significant (n=16 pairs). Our findings suggest that the site of the nerve is consistent between and within subjects for sex and age, but not for dentate status. The association between the nerve and the lingual plate varied, which suggests that care must be taken when operating in the area.

Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery.

Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para-aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site-modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co-administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5-AS from prodrugs including balsalazide.

CYP2D6 in the brain: genotype effects on resting brain perfusion.

The cytochrome P450 2D6 (CYP2D6) is a genetically polymorphic enzyme involved in the metabolism of several psychoactive drugs. Beside its expression in the liver, CYP2D6 is highly expressed in several regions of the brain, such as the hippocampus, thalamus, hypothalamus and the cortex, but its function in the brain is not well understood. The CYP2D6 enzyme may also have a physiological role due to its involvement in neurotransmitter biotransformation. In this study, CYP2D6 genotyping was performed in N=188 healthy individuals and compared with brain perfusion levels at rest, which may reflect an ongoing biological process regulating the reactivity of the individual to emotional stimuli and the detection of signals evoking fear. Relative to N=42 matched extensive metabolizers, N=14 poor metabolizers were associated with 15% higher perfusion levels in the thalamus (P=0.03 and 0.003). Effects were also present in the whole (N=188) sample divided into metabolizer groups, or finely graded into seven CYP2D6 activity levels. A weaker effect was observed in the right hippocampus (P=0.05). An exploratory analysis, extended to the whole brain, suggested the involvement of CYP2D6 in regions associated with alertness or serotonergic function. These findings support the hypothesis of a functional role of CYP2D6 in the brain.

Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus.

AIMS/HYPOTHESIS: We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus. METHODS: KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intra-muscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA(1c) and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied. RESULTS: Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA(1c), cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant. CONCLUSIONS/INTERPRETATION: Human skeletal myoblast transplantation attenuated hyperglycaemia and hyperinsulinaemia and improved glucose tolerance in the KK mouse. This novel approach of improving muscle insulin resistance may be a potential alternative treatment for type 2 diabetes mellitus.

Direct costs of myopia in Singapore.

AIMS: To estimate the direct costs of myopia in Singapore children. METHODS: A cross-sectional study of 377 Singaporean school children aged 12-17 years from one school in Singapore Cohort study of the Risk factors for Myopia (SCORM) was conducted. A combination of parent and self-administered questionnaires asked about the cost of each optometrist visit, spectacles, and contact lenses, transport costs, father's educational level, and total family income. RESULTS: A total of 377 subjects participated and cost data were available from 301 subjects. The mean annual direct cost of myopia was S$221.7+/-313.7 (CI, S$186.5-258.1) or US$147.8+/-209.1 (CI, US$124.3-172.1) and median annual direct cost of myopia was S$125.0 or US$83.3. The mean cost per pair of spectacles was S$123.2+/-61.2 (CI, S$116.6-129.8) or US$82.1+/-40.8 (CI, US$77.8-86.5). Sixty subjects (15.9%) wore contact lenses. The mean annual cost of contact lenses was S$567.1+/-565.7 (CI, S$422.2-712.0) or US$378.1+/-377.1 (CI, US$281.4-474.6). Subjects of families with higher total family income and those with fathers with secondary or higher education had higher annual direct expenditure (P=0.03 and P=0.001 respectively). Subjects from families with higher household incomes had higher frequency of change of spectacles (P=0.02) and shorter time since the last change of spectacles (P=0.03). CONCLUSIONS: The mean annual direct cost of myopia for Singapore school children was S$221.68 (US$148) and the median, S$125.00 (US$83.33) per subject. Myopia is associated with significant financial burden in Singapore.

Corneal biomechanics, thickness and optic disc morphology in children with optic disc tilt.

AIMS: To determine the associations between corneal biomechanical parameters as measured by the Reichert Ocular Response Analyser (ORA) and disc morphology and retinal nerve fibre layer thickness (RNFL) measured by the Heidelberg Retinal Tomograph (HRT) II in Singaporean children. METHODS: This is a cross-sectional study conducted on a subset of children enrolled in the Singapore Cohort Study of the Risk Factors of Myopia (SCORM). Corneal hysteresis (CH), corneal resistance factor (CRF) and central corneal thickness (CCT) were measured with the ORA. Optic disc morphology and RNFL thickness were assessed by the HRT II. Cycloplegic refraction and ultrasound A-scans were also performed, and disc tilt was assayed from stereo photographs. RESULTS: 102 subjects (mean age 12.01 (SD 0.57) years; range 11-14 years) were included in the study. The mean CH was 12.00 (1.40) mm Hg, the mean CRF was 11.99 (1.65) mm Hg, and the mean CCT was 581.12 (33.53) mum. Eyes with tilted discs had significantly longer axial lengths and more myopic refraction than eyes without tilted discs. There were no significant correlations between CH, CRF or CCT and the HRT II parameters, after the application of the Bonferroni correction. When stratified for disc tilt, however, the global disc area was significantly correlated with CCT (r = -0.49, p = 0.001). CONCLUSION: Corneal biomechanical properties as measured with the ORA do not vary with optic disc parameters or RNFL. Central corneal thickness is correlated with disc area in Singaporean schoolchildren with tilted discs. This relationship may influence glaucoma risk in myopic subjects.

Inhaled corticosteroids for stable chronic obstructive pulmonary disease.

BACKGROUND: The role of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) has been the subject of much controversy. Major international guidelines recommend selective use of ICS. Recently published meta-analyses have reported conflicting findings on the effects of inhaled steroid therapy in COPD. OBJECTIVES: The objective of the review is to determine the efficacy of regular use of inhaled corticosteroids in patients with stable COPD. SEARCH STRATEGY: A pre-defined search strategy was used to search the Cochrane Airways Group specialised register for relevant literature. Searches are current as of October 2006. SELECTION CRITERIA: We selected randomised trials comparing any dose of any type of inhaled steroid with a placebo control in patients with COPD. Acute bronchodilator reversibility to short term beta2-agonists and bronchial hyperresponsiveness were not exclusion criteria. The a priori primary outcome was change in lung function. Data on mortality, exacerbations, quality of life and symptoms, rescue bronchodilator use, exercise capacity, biomarkers and safety were also analysed. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Forty-seven primary studies with 13,139 participants met the inclusion criteria. Medium term use of ICS (> two months and up to six months) resulted in a small improvement in FEV1 in some studies. Long term use of ICS (> six months) did not significantly reduce the rate of decline in FEV1 in COPD patients (weighted mean difference (WMD) 5.80 ml/year with ICS over placebo, 95% CI -0.28 to 11.88, 2333 participants). There was no statistically significant effect on mortality in COPD patients (OR 0.98, 95% CI 0.83 to 1.16, 8390 participants). Long term use of ICS reduced the mean rate of exacerbations in those studies where pooling of data was possible (WMD -0.26 exacerbations per patient per year, 95% CI -0.37 to -0.14, 2586 participants). ICS slowed the rate of decline in quality of life, as measured by the St George's Respiratory Questionnaire (WMD -1.22 units/year, 95% CI -1.83 to -0.60, 2507 participants). Response to ICS was not predicted by oral steroid response, bronchodilator reversibility or bronchial hyper-responsiveness in COPD patients. There was an increased risk of oropharyngeal candidiasis (OR 2.49, 95% CI 1.78 to 3.49, 4380 participants) and hoarseness. The few long term studies that measured bone effects generally showed no major effect on fractures and bone mineral density over 3 years. AUTHORS' CONCLUSIONS: Patients and clinicians should balance the potential benefits of inhaled steroids in COPD (reduced rate of exacerbations, reduced rate of decline in quality of life), against the known increase in local side effects (oropharyngeal candidiasis and hoarseness). The risk of long term adverse effects is unknown.

Structure and mechanism of arylamine N-acetyltransferases.

Arylamine N-acetyltransferases (NATs) are a family of phase II drug-metabolising enzymes which are important in the biotransformation of various aromatic and heterocyclic amines and hydroxylamines, arylhydrazines and arylhydrazides. NATs are present in a wide range of eukaryotes and prokaryotes. Humans have two functional NAT isoforms, both of which are highly polymorphic. The pharmacogenetics of NATs is an area which has been extensively studied. The determination of the X-ray crystal structure of NAT from Salmonella typhimurium led to the identification of the catalytically essential triad of residues: Cys-His-Asp, which is present in all functional NAT enzymes. Recent co-crystallisation data and in silico docking studies of NAT from Mycobacterium smegmatis with substrates and inhibitors have aided the identification of important contact residues within the active site. The X-ray crystal structures of four prokaryotic NAT proteins have now been determined, and these have been used to generate structural models of eukaryotic NATs, providing valuable insight into their active-site architecture. In addition to aiding crystallographic experiments, recent progress in the production of recombinant prokaryotic and eukaryotic NATs has allowed comparative studies of the kinetics and activity profiles of these enzymes. In this review we present an overview of recent structural and activity studies on NAT enzymes, and we outline how in silico methods may be used to predict NAT protein-ligand interactions based on the current knowledge.

Off-pump coronary artery bypass grafting is a safe and effective treatment modality for Asian patients requiring coronary revascularisation.

INTRODUCTION: Off-pump coronary artery bypass grafting (OPCABG) is gaining widespread acceptance as the preferred choice for myocardial revascularisation. However, no definite data exist as to whether it is better than conventional CABG. We aimed to study the efficacy of the procedure in our patients, which constituted of a predominantly Asian population. METHODS: Between January 2000 and December 2002, 1062 patients underwent isolated coronary artery bypass in our institution. 184 patients (17.3 percent) underwent OPCABG. Patients were preoperatively prospectively risk stratified under the EuroSCORE risk assessment model under high, medium and low risk classes thereby making them comparable. Post-operative complications, intensive care unit stay, hospital stay, types of grafts done were then analysed in these different risk classes. RESULTS: The incidence of off-pump procedures showed a gradual increase over the last three years in this institution. A reduction in the number of post-operative complications, hospital stay, intensive care unit stay and mortality in the off-pump group was observed. Certain differences were found to be statistically significant. CONCLUSION: Off-pump CABG is a safe and viable alternative to conventional CABG as a treatment modality for surgical coronary revascularisation.

Human VEGF165-myoblasts produce concomitant angiogenesis/myogenesis in the regenerative heart.

Bioengineering the regenerative heart may provide a novel treatment for heart failure. On May 14, 2002, a 55-year-old man suffering from ischemic myocardial infarction received 25 injections carrying 465 million cGMP-produced pure myoblasts into his myocardium after coronary artery bypass grafting. As on August 28, 2002, his EKG was normal and showed no arrhythmia. His ejection fraction increased by 13%. He no longer experienced shortness of breath and angina as he did before the treatment. Three myogenesis mechanisms were elucidated with 17 human/porcine xenografts using cyclosporine as immunosuppressant. Some myoblasts developed to become cardiomyocytes. Others transferred their nuclei into host cardiomyocytes through natural cell fusion. As yet others formed skeletal myofibers with satellite cells. De novo production of contractile filaments augmented the heart contractility. Human myoblasts transduced with VEGF165 gene produced six times more capillaries in porcine myocardium than in placebo. Xenograft rejection was not observed for up to 20 weeks despite cyclosporine discontinuation at 6 weeks. Pros and cons of autografts vs. allografts are compared to guide future development of heart cell therapy.

Deep hypothermic circulatory arrest in adults undergoing aortic surgery: local experience.

INTRODUCTION: The aim of our study was to evaluate the efficacy and safety of deep hypothermic circulatory arrest (DHCA) as a method of cerebral protection during aortic surgery. MATERIALS AND METHODS: We carried out a retrospective review of 59 consecutive patients (48 men, 11 women) undergoing elective or emergency aortic surgery requiring DHCA from January 1999 to April 2002 in 2 tertiary care hospitals. Data regarding demographics, clinical characteristics, operation type, duration of circulatory arrest, nasopharyngeal temperatures, use of retrograde cerebral perfusion and central nervous system (CNS) morbidity and perioperative mortality were collected and analysed. RESULTS: There were 47 (79.7 %) operations for aortic dissections and 12 (20.3 %) for aortic aneurysms. The mean duration of circulatory arrest was 42 +/- 23 minutes. The lowest nasopharyngeal temperature at the time of arrest was 16.5 degrees +/- 1.9 degrees C. Eight (13.6 %) patients had a new irreversible neurologic deficit postoperatively. These patients had a mean circulatory arrest time of 50 +/- 28 minutes. Temporary neurologic dysfunction occurred in 8 (13.6 %) patients. Intra-hospital mortality was 22 %. The mean circulatory arrest time for patients who died was 54 +/- 24 minutes. CONCLUSION: DHCA is a simple and effective method of CNS protection in aortic surgery with satisfactory outcomes. With increased surgical and anaesthetic experience, as well as selective use of adjuncts of cerebral protection, reductions in mortality and neurological morbidity will likely be achieved in the future.

Effectiveness of transient immunosuppression using cyclosporine for xenomyoblast transplantation for cardiac repair.

We studied the survival of human myoblast for cellular myocardial reconstruction in a porcine model of chronic myocardial ischemia with immune tolerance using transient immunosuppression. A porcine model of chronic cardiac ischemia was created in 10 pigs (DMEM medium-injected n = 4; myoblast transplanted n = 6) by clamping ameroid ring around left circumflex coronary artery. Three weeks later, 3 x 10(8) human myoblasts carrying lac-z reporter gene were transplanted in multiple sites (0.25 mL each) into the left ventricular wall. Immunosuppression was achieved with 5 mg/kg cyclosporine for 6 weeks after cell transplantation. After animals were euthanized between 6 and 30 weeks after cell transplantation; the heart was removed for histological studies. Discontinuation of immunosuppression after 6 weeks of cell transplantation did not result in donor cell rejection. The lac-z-positive donor cells were detected in porcine host cardiac tissue for up to 30 weeks posttransplantation, expressing human skeletal myosin heavy chain. The results highlight the effectiveness of transient immunosuppression for myoblast transplantation for cardiac repair.

Human VEGF165-myoblasts produce concomitant angiogenesis/myogenesis in the regenerative heart.

Bioengineering the regenerative heart may provide a novel treatment for heart failure. On May 14, 2002, a 55-year-old man suffering from ischemic myocardial infarction received 25 injections carrying 465 million cGMP-produced pure myoblasts into his myocardium after coronary artery bypass grafting. As on August 28, 2002, his EKG was normal and showed no arrhythmia. His ejection fraction increased by 13%. He no longer experienced shortness of breath and angina as he did before the treatment. Three myogenesis mechanisms were elucidated with 17 human/porcine xenografts using cyclosporine as immunosuppressant. Some myoblasts developed to become cardiomyocytes. Others transferred their nuclei into host cardiomyocytes through natural cell fusion. As yet others formed skeletal myofibers with satellite cells. De novo production of contractile filaments augmented the heart contractility. Human myoblasts transduced with VEGF165 gene produced six times more capillaries in porcine myocardium than in placebo. Xenograft rejection was not observed for up to 20 weeks despite cyclosporine discontinuation at 6 weeks. Pros and cons of autografts vs. allografts are compared to guide future development of heart cell therapy. (Mol Cell Biochem 263: 173-178, 2004).

Generation and analysis of mice with a targeted disruption of the arylamine N-acetyltransferase type 2 gene.

Arylamine N-acetyltransferases (NATs) are polymorphic xenobiotic metabolising enzymes, linked to cancer susceptibility in a variety of tissues. In humans and in mice there are multiple NAT isoforms. To identify whether the different isoforms represent inbuilt redundancy or whether they have unique roles, we have generated mice with a null allele of Nat2 by gene targeting. This mouse line conclusively demonstrates that the different isoforms have distinct functions with no compensatory expression in the Nat2 null animals of the other isoforms. In addition, we have used the transgenic line to show the pattern of Nat2 expression during development. Although Nat2 is not essential for embryonic development, it has a widespread tissue distribution from at least embryonic day 9.5. This mouse line now paves the way for the teratological role of Nat2 to be tested.

Arylamine N-acetyltransferases: a pharmacogenomic approach to drug metabolism and endogenous function.

The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. The NATs have been shown to be important in drug detoxification and carcinogen activation, with humans possessing two isoenzymes encoded by polymorphic genes. This polymorphism has pharmacogenetic implications, leading to different rates of inactivation of drugs, including the anti-tubercular agent isoniazid and the anti-hypertensive drug hydralazine. Mice provide a good model for human NAT, allowing genetic manipulation of expression to explore possible endogenous roles of these enzymes. The first three-dimensional NAT structure was resolved for NAT from Salmonella typhimurium, and subsequently the structure of NAT from Mycobacterium smegmatis has been elucidated. These identified a 'Cys-His-Asp' catalytic triad (conserved in all NATs), which is believed to be responsible for the activation of the active site cysteine residue. As more genomic data become available, NAT homologues continue to be found in prokaryotic species, many of which are pathogenic, including Mycobacterium tuberculosis. The discovery of NAT in M. tuberculosis is particularly significant, since this enzyme participates in inactivation of isoniazid in the bacterium, with implications for isoniazid resistance. Structural studies on NAT proteins and phenotypic analyses of organisms (both mice and prokaryotes) following genetic modifications of the nat genes are leading to an understanding of the potentially diverse roles of NAT in endogenous and xenobiotic metabolism. These studies have indicated that NAT, particularly in Mycobacteria, has the potential to be a drug target. Combinatorial chemical approaches, together with in silico structural studies, will allow for advances in the identification of NAT substrates and inhibitors, both as experimental tools and as potential drugs.