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Biomedical subjects

A Upton

Publications and source records attributed to A Upton.

At least 19 recordsLinked to original sources
PubMed2003

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.

Animals↗
PubMed2003

Mupirocin and Staphylococcus aureus: a recent paradigm of emerging antibiotic resistance.

OBJECTIVES: To describe trends in mupirocin resistance among Staphylococcus aureus in New Zealand (NZ), following the availability of mupirocin in 1986. PATIENTS AND METHODS: Data from a variety of sources were used for this study: susceptibility data collected annually from diagnostic laboratories throughout NZ; a local survey of mupirocin-resistant S. aureus in the Auckland area in 1997; a national survey of S. aureus antimicrobial susceptibility in 1999; and the national methicillin-resistant S. aureus (MRSA) surveillance programme. RESULTS: All data sources show that there was a steady increase in mupirocin resistance among S. aureus throughout the 1990s, and rates in NZ are now markedly higher than those reported in most other comparable countries. By 1999, resistance averaged 28%, with higher rates among community-acquired compared with hospital-acquired isolates, and with a wide geographical variation in resistance. Resistance was more common among S. aureus generally than MRSA. CONCLUSION: We postulate that the steady rise in mupirocin resistance among S. aureus in NZ throughout the 1990s may be due, at least in part, to the over the counter availability of mupirocin from 1991 to 2000. The current patterns of mupirocin consumption need to be reviewed and its use rationalized to maximize the chances of this antibiotic retaining beneficial antistaphylococcal activity.

Community-Acquired Infections↗
PubMed2001

Afferent vagal modulation. Clinical studies of visceral sensory input.

UNLABELLED: The frequency composition of a continuous time series of R-R intervals may be viewed as the phasic output of a central processing system intimately dependent on sensory input from a variety of afferent sources. While different measures of heart rate variability permit a glimpse into the autonomic efferent limb of this complex system, direct access of afferent fibers in humans has remained elusive. Using a specially designed esophageal catheter/manometer probe, we have been able to gain access to vagal afferent fibers in the distal esophagus. Our studies on the effect of vagal afferent electrostimulation on both cerebral evoked potentials (EvP) and the power spectrum of heart rate variability have yielded the following observations: 1. Stimulation of esophageal vagal afferents dramatically and reproducibly increases the high frequency (HF) vagal power and reduces the low frequency (LF) power of the heart rate autospectrum. 2. This effect is constant across stimulation frequencies from 0.1 to 1.0 Hz and across stimulation intensities from 2.5 to 20 mA. 3. Regardless of the stimulation parameters, there are only minimal changes in heart rate (2-6 bpm) and no change in respiratory frequency. 4. There is a linear correlation between electrical stimulation intensity and the amplitude of cerebral evoked potentials, whereas there is a non-linear relationship with all short-term power spectral indices. 5. While cerebral evoked potentials are only elicited at stimulation intensities above perception threshold, there is already a significant shift to increased vagal efferent modulation well below perception threshold. CONCLUSION: These studies support the concept that power spectral indices of heart rate variability represent phasic output responses to tonic afferent viscerosensory signals in humans. These studies also demonstrate the feasibility of accessing vagal afferents in humans.

Evoked Potentials, Somatosensory↗
PubMed2001

Arylamine N-acetyltransferases - of mice, men and microorganisms.

Arylamine N-acetyltransferases (NATs) catalyse the transfer of an acetyl group from acetyl CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. These enzymes are polymorphic and have an important place in the history of pharmacogenetics, being first identified as responsible for the polymorphic inactivation of the anti-tubercular drug isoniazid. NAT has recently been identified within Mycobacterium tuberculosis itself and is an important candidate for modulating the response of mycobacteria to isoniazid. The first three-dimensional structure of the unique NAT family shows the active-site cysteine to be aligned with conserved histidine and aspartate residues to form a catalytic triad, thus providing an activation mechanism for transfer of the acetyl group from acetyl CoA to cysteine. The unique fold could allow different members of the NAT family to play a variety of roles in endogenous and xenobiotic metabolism.

Alleles↗
PubMed2000

Placental arylamine N-acetyltransferase type 1: potential contributory source of urinary folate catabolite p-acetamidobenzoylglutamate during pregnancy.

Human arylamine N-acetyltransferase type 1 (NAT1), better known as a drug-metabolising enzyme, has been proposed to acetylate the folate catabolite p-aminobenzoylglutamate (p-abaglu) to N-acetamidobenzoylglutamate (ap-abaglu) which is a major urinary folate catabolite. Using mass spectroscopic analysis, we demonstrate the formation of ap-abaglu by recombinant human NAT1 and human placental homogenates. Using density gradient centrifugation the placental enzymic activity which acetylates p-aba and the placental enzymic activity acetylating p-abaglu both have an S(20,w) value of 3.25 S. This is the expected value for a monomer of human NAT1 (33 kDa). The specific NAT1 inhibitor 5-iodosalicylate inhibits acetylation of both p-aba and p-abaglu catalysed by either recombinant human NAT1 or placental samples as the source of enzyme. These data demonstrate that NAT1 is the major placental enzyme involved in acetylating p-abaglu.

4-Aminobenzoic Acid↗
PubMed2000

Expression of arylamine N-acetyltransferases in pre-term placentas and in human pre-implantation embryos.

Arylamine N -acetyltransferases (NATs) catalyse the acetylation from acetyl-CoA of arylamines and hydrazines. There are two human isoenzymes which show polymorphism, and both enzymes are involved in the activation and detoxification of environmental carcinogens and teratogens. The two human isoenzymes NAT1 and NAT2 show different tissue distribution, with human NAT2 being found in liver and intestine whilst human NAT1 is expressed in many tissues including erythrocytes, bladder, lymphocytes and neural tissue, as well as liver and intestine. It has been proposed that NAT1 has an endogenous role in the acetylation of the folate catabolite p -aminobenzoyl-L-glutamate (pABGlu) to produce the major urinary product, N -acetyl-pABGlu. The murine homologue of human NAT1 is known to be concentrated in the neural tube during development. We show here that human NAT1 but not human NAT2 is expressed in pre-implantation embryos at the blastocyst stage and show that NAT1 is also expressed in early human placenta at the earliest available stage, 5.5 weeks. We demonstrate that there is inter-individual variation in NAT1 expression. In view of the role of folate in protecting against neural tube defects, we propose that NAT1 is a candidate risk factor for susceptibility to neural tube defects.

Acetylation↗
PubMed1999

A method for genotyping murine arylamine N-acetyltransferase type 2 (NAT2): a gene expressed in preimplantation embryonic stem cells encoding an enzyme acetylating the folate catabolite p-aminobenzoylglutamate.

Mice have three arylamine N-acetyltransferase (NAT) isoenzymes (NAT1, NAT2, and NAT3) of which NAT2 is known to be polymorphic. Humans have two polymorphic isoenzymes, NAT1 and NAT2. The isoenzymes mouse NAT1 and human NAT2 are expressed predominantly in the liver and intestine and are involved in drug and xenobiotic metabolism. Mouse NAT2 and human NAT1 have a widespread tissue distribution and the folate catabolite p-aminobenzoylglutamate (pAB-Glu) has been proposed as a candidate endogenous substrate. All mice have detectable NAT2 activity, although inbred mouse strains have either a fast or slow acetylator phenotype conferred by the presence of either NAT2*8 (fast) or NAT2*9 (slow) alleles at the NAT2 locus. In this report, we describe a simple method for distinguishing these murine alleles by polymerase chain reaction followed by restriction fragment length polymorphism analysis. We compared the tissue distribution of the acetylation activity found in both fast (C57BL/6J) and slow (A/J) acetylating strains of mice using pAB-Glu and p-aminobenzoic acid as probe substrates. It has previously been demonstrated that murine NAT2 is expressed in the neural tube prior to closure (Stanley L, Copp A, Rolls S, Smelt V, Perry VH and Sim E, Teratology 58: 174-182, 1998). We demonstrate here that murine NAT2 is expressed in preimplantation embryonic stem cells. Murine NAT2 is likely to be expressed prior to neurulation and this may be important in view of the protective role of folate in neural tube development.

4-Aminobenzoic Acid↗
PubMed1994

The private funding of public research. New directions in the administration of occupational and environmental health research.

Dr. Cullen: The experience with the new research models, starting with the prototypic experience of the rubber industry studies of the 1970s and expanding to diverse sectors of American industry in the 1980s, has yielded some important lessons for the future. In closing this symposium I shall try to summarize these briefly. Certain strengths of the evolving process seem common to each of the models. Alone and collectively, the new research arrangements have quite apparently served to increase substantially the pool of funds available to the academic sector for the study of occupational health and safety problems. As a consequence, a larger pool of investigators has participated in the research process, greatly strengthening the future academic capability and experience of our fragilely supported teaching centers. Combined with the involvement of the academic centers in the review process, there has been an undeniable broadening and deepening of the nation's research output and long-term capability in occupational health. On the side of the private sector, the new relationships have led to marked progress in the knowledge base about health and safety problems, with a heavily directed focus on those of greatest relevance to the industries involved. The credibility of the knowledge acquired has been enhanced, an important achievement in a society in which perception of truth is often as important as the truth itself! Because of the requirements of the process for broad involvement by the organizations which undertake these activities, health and safety have achieved far greater visibility and attention by corporate and union leaders who may have previously had no involvement in issues of health and safety.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1991

Balance and cognitive impairment in two epileptic patients before and after vagal nerve stimulation.

Balance and cognition were assessed in two patients with uncontrolled complex partial seizures. The patients were on anticonvulsant medications and were treated with left vagal stimulation. Balance and cognition were assessed before and after vagal stimulation, and the results were compared with age matched controls and older patients with Parkinson's disease. Severe impairments of function were found in the epileptic patients, and such negative effects of medication make vagal stimulation a potentially practical alternative treatment for uncontrolled epilepsy.

Adult↗
PubMed1987

Multiple sclerosis in childhood: clinical profile in 125 patients.

Multiple sclerosis (MS) has its usual onset in early adult life (average age of 30 years), but age at clinical onset varies considerably. The implications of the age of onset on the clinical presentation and course of MS are unclear. This population-based retrospective study presents data from a group of 125 patients with onset of MS before age 16 years and can thus be considered as representative of MS occurring in childhood. It demonstrates that childhood MS is more frequent in girls, that it very often has a relapsing-remitting course, that initial bouts usually involve afferent structures of the central nervous system, that recovery from these is often complete, and that the pace of the disease is slow.

Adolescent↗
PubMed1983

A double-blind crossover study of cinromide versus placebo in epileptic outpatients with partial seizures.

Cinromide was evaluated versus placebo as add-on therapy in a double-blind crossover study in epileptic outpatients with partial seizures at three sites. Four-week base lines were used before, between, and after the two 12-week treatment periods of the crossover. An operational definition was used to classify each partial seizure as Type A, B, or C. Doses of concurrent antiepileptic drugs were adjusted to maintain pretreatment therapeutic plasma levels. Doses of cinromide ranged from 1,200 to 4,800 mg/day, depending on patient response. Seven patients were withdrawn from the study because of adverse experiences (two receiving placebo and five receiving cinromide). Twenty-eight patients completed the entire 36-week study. A decrease in the average frequency of seizures/week was observed in 12 patients receiving cinromide and in 16 patients receiving placebo. The median frequencies with cinromide and placebo were 3.3 and 2.9 seizures/week, respectively (median initial base-line frequency 3.5 seizures/week for all 28 patients). Although patients were randomly assigned to receive either cinromide or placebo first, the median base-line seizure frequency was greater at the start of the first treatment period in the cinromide group (4.3 versus 2.5 seizures/week) and greater at the start of the second treatment period in the placebo group (3.8 versus 1.4). The median seizure frequency in each higher group decreased with treatment, whereas it increased in each of the lower groups. This study did not demonstrate a beneficial effect of cinromide over placebo for Type A, B, or C partial seizures. The data suggested the presence of an oscillation of seizure frequency in our population of epileptic patients having partial seizures, as well as a placebo effect. No significant carry-over effects were observed. Cinromide has previously been shown to have significant antiepileptic activity in various animal models of epilepsy. The lack of an antiepileptic response to cinromide in humans may have been due to factors other than species differences but indicates that a positive results of a drug in animal models is not the sole factor necessary to predict beneficial antiepileptic activity in humans.

Adolescent↗
PubMed1975

Patterns of motoneuron dysfunction and recovery.

Electrophysiological studies have been carried out on five patients with neuropathies of different etiologies. In each patient serial estimates were made of the numbers of functioning motor units in various muscles. It was found that the intensity of the neuropathic process and the rate of recovery differed in a consistent way among the motoneuron pools investigated. The lesion was more severe in extensor digitorum brevis neurons than in thenar neurons, while the hypothenar ones were least affected. A stage of partial synaptic failure has been recognized in which a motoneuron appears to be no longer able to excite a muscle fiber, but still capable of maintaining certain trophic activities. By comparing the number of functioning motor units with the size of the maximum evoked muscle response it has been possible to detect the adoption of denervated muscle fibers by axonal sprouts from 'healthy' surviving neurons (collateral reinnervation). Lastly, in some muscles it appears that the adopted muscle fibers may subsequently be recaptured by the original motoneurons following recovery of the latter from the neurotoxic insult.

Adult↗
PubMed1974

Large electroencephalographic responses and their relationship to cleido-cranial dysplasia.

We have reported six individuals (five certain heterozygotes for cleido-cranial-dysostosis and one possible heterozygote) who have unusual EEG findings, consisting of very large responses to photic flash stimulation at very low stimulus rates. Such visual responses are extremely rare and have not been seen before in the experience of an EEG department over 12 years and they were not seen in 98 control subjects. It is likely that these responses are an irregular manifestation of the gene for cleido-cranial-dysplasia, and that the responses are independent of skull deformity. One importance of these responses is their demonstration in neurologically normal individuals for previously such large responses have only been reported in association with neurolipidosis. They may have neurophysiological significance in that they may reflect an unusual balance between inhibitory and excitatory mechanisms in the nervous system.

Adolescent↗