Search PubMed⌕ Search

Biomedical subjects

M Hutton

Publications and source records attributed to M Hutton.

At least 109 records · Page 6Linked to original sources
PubMed1996

Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid beta-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these mutations and controls. A beta 1-42(43) was elevated in plasma from subjects with FAD-linked PS1 (P < 0.0001), PS2N1411 (P = 0.009), APPK670N,M671L (P < 0.0001), and APPV7171 (one subject) mutations. A beta ending at A beta 42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Alzhelmer's disease by increasing the extracellular concentration of A beta 42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.

Alzheimer Disease↗
PubMed1996

Secondary prevention of cancer.

In recent years prevention has become extremely important in the war against cancer. For many cancers, major risk factors are not amenable to change and, therefore, secondary prevention through screening and early detection is the major type of intervention. Furthermore, with the discovery of cancer genes and tumor markers, which make it easier than ever before to identify people with increased risk of developing certain types of cancers, the role of secondary prevention has assumed an even greater value. This paper reviews recent advances in secondary prevention of those cancers for which overall efficacy of screening to reduce mortality has been demonstrated but for which some residual controversies exist: breast, cervical, and colorectal cancers.

Breast Neoplasms↗
PubMed1996

The association between occupation and tuberculosis. A population-based survey.

There has been increasing interest in the potential association between occupation and the risk of tuberculosis. Therefore, we analyzed occupational information collected on all patients with clinically active tuberculosis in 29 states from 1984 to 1985. Census data were used to estimate the number of persons in each of the occupations. Information on employment and occupation was ascertained for 9,534 (99%) of the working age (16 through 64 yr) tuberculosis patients. The overall case rate of tuberculosis in this age group in the study areas was 8.4 per 100,000 persons, which was slightly lower than the national rate of 9.3 per 100,000 persons. As a group, health care workers had rates of tuberculosis similar to the general population (standardized morbidity ratio [SMR]: 1.0; 95% CI: 0.9 to 1.1). However, elevated rates were observed for inhalation therapists (SMR: 2.9; 95% CI: 1.2 to 6.0), and lower-paid health care workers (SMR: 1.3; 95% CI: 1.1 to 1.5). Elevated rates were also noted for funeral directors (SMR: 3.9; 95% CI: 2.2 to 6.1) and farm workers (SMR: 3.7; 95% CI: 3.4 to 4.1). These data suggest that even in communities with relatively low rates of tuberculosis certain occupations may be associated with an elevated risk.

Adolescent↗
PubMed1996

The role of presenilin 1 in the genetics of Alzheimer's disease.

Approximately 75% of AD patients have an onset of the disease after the age of 60 years, and 60% of AD patients have no family history of the disease. Some cases of EOAD are clearly inherited in an autosomal-dominant manner. The beta APP gene on chromosome 21, the PS-1 gene on chromosome 14, and the PS-2 gene on chromosome 1 have all been characterized as genes in which mutations lead to familial EOAD. For LOAD, the work on ApoE indicates that the epsilon 4 allele is a risk factor for developing AD. However, 35-50% of all AD patients do not have an epsilon 4 allele. Other loci contributing to LOAD remain to be mapped and characterized. As in other complex disorders, these additional loci may involve genetic interactions with the known AD loci. Identification of all susceptibility loci for AD is a major goal in resolving the pathogenesis of AD.

Alternative Splicing↗
PubMed1995

The involvement of NADP(H) binding and release in energy transduction by proton-translocating nicotinamide nucleotide transhydrogenase from Escherichia coli.

Proton-translocating transhydrogenase was solubilised and purified from membranes of Escherichia coli. Consistent with recent evidence [Hutton, M., Day, J., Bizouarn, T. and Jackson, J.B. (1994) Eur. J. Biochem. 219, 1041-1051], at low pH and salt concentration, the enzyme catalysed rapid reduction of the NAD+ analogue AcPdAD+ by a combination of NADH and NADPH. At saturating concentrations of NADPH, the dependence of the steady-state rate on the concentrations of NADH and AcPdAD+ indicated that, with respect to these two nucleotides, the reaction proceeds by a ping-pong mechanism. High concentrations of either NADH or AcPdAD+ led to substrate inhibition. These observations support the view that, in this reaction, NADP(H) remains bound to the enzyme: AcPdAD+ is reduced by enzyme-bound NADPH, and NADH is oxidised by enzyme-bound NADP+, in a cyclic process. When this reaction was carried out with [4A-2H]NADH replacing [4A-1H]NADH, the rate was decreased by 46%, suggesting that the H- transfer steps are rate-limiting. In simple 'reverse' transhydrogenation, the reduction of AcPdAD+ was slower with [4B-2H]NADPH than with [4B-1H]NADPH when the reaction was performed at pH 8.0, but there was no deuterium isotope effect at pH 6.0. This indicates that H- transfer is rate-limiting at pH 8.0 and supports our earlier suggestion that NADP+ release from the enzyme is rate-limiting at low pH. The lack of a deuterium isotope effect in the reduction of thio-NADP+ by NADH at low pH is also consistent with the view that NADPH release from the enzyme is slow under these conditions. A steady-state rate equation is derived for the reduction of AcPdAD+ by NADPH plus NADH, assuming operation of the cyclic pathway. It adequately accounts for the pH dependence of the enzyme, for the features described above and for kinetic characteristics of E. coli transhydrogenase described in the literature.

Escherichia coli↗
PubMed1995

Properties of the soluble polypeptide of the proton-translocating transhydrogenase from Rhodospirillum rubrum obtained by expression in Escherichia coli.

Transhydrogenase, which catalyses the reduction of NADP+ by NADH coupled to proton translocation across a membrane, may be unique in the photosynthetic bacterium Rhodospirillum rubrum. Unlike the homologous enzyme from animal mitochondria and other bacterial sources, it has a water-soluble polypeptide, which exists as a dimer (Ths), that can be reversibly dissociated from the membrane component [Williams, R., Cotton, N. P. J., Thomas, C. M. & Jackson, J. B. (1994) Microbiology, 140, 1595-1604]. We have expressed the gene for Ths in cells of Escherichia coli under control of the tac promoter and a strong ribosome binding site. The protein, purified by column chromatography, fully reconstituted transhydrogenation activity to everted membrane vesicles of Rhs. rubrum that had been washed to remove Ths. The purified expressed protein was prepared in quantities over 100-fold greater than were obtained from wild-type Rhs. rubrum. The fluorescence spectrum of purified expressed Ths had an intense and unusually short wavelength emission maximum at 310 nm with shoulders at 298 and 322 nm. Time-resolved measurements indicated that the fluorescence decay was almost monoexponential with a lifetime of 5.2 ns. On denaturation with 4 M guanidine hydrochloride, the emission band shifted to 352 nm and decreased in intensity. In the native protein, the fluorophore was relatively inaccessible to quenching solutes, such as iodide ions and acrylamide. It is concluded that the fluorescence emission arises mainly from the single tryptophan residue of Ths (Trp72), which is locked into a rigid conformation and is located in highly non-polar environment. The 310-nm fluorescence of Ths was quenched by NADH, maximally to 46%. The apparent binding constant was 18 microM. The fluorescence of Ths-bound NADH was enhanced relative to the nucleotide in free solution and its emission maximum was shifted to a shorter wavelength (440 nm). These data support previous indications that the NADH binding site is located in domain I of proton-translocating transhydrogenase. Excitation of Ths at 280 nm did not lead to sensitized emission at 440 nm from bound NADH. This indicates that the quenching of fluorescence of Ths by NADH does not result from resonance energy transfer from Trp72 to the bound nucleotide. NAD+, NADP+ and NADPH had little effect on the protein fluorescence. The kinetics of quenching of Ths fluorescence by NADH were examined after mixing in a stopped-flow device. The 'on' rate constant for nucleotide binding was approximately 8 x 10(6) M-1 s-1 and the 'off' constant approximately 150 s-1.

Amino Acid Sequence↗
PubMed1995

Butyrate metabolism in the terminal ileal mucosa of patients with ulcerative colitis.

The rate of oxidation of butyrate, glutamine and glucose was investigated in terminal ileal mucosal biopsy samples from nine patients with ulcerative colitis undergoing restorative proctocolectomy and from 12 patients undergoing laparotomy for reasons other than ulcerative colitis. Substrate oxidation was assayed using a radiolabelled isotope technique. Butyrate was the preferred fuel substrate, followed by glutamine and then glucose (median (95 per cent confidence interval) 567 (262-894), 63 (35-123) and 8.1 (5.1-18) pmol micrograms-1 h-1 respectively; P < 0.01, Mann-Whitney U test) in normal terminal ileal mucosa. The patients with ulcerative colitis had a significantly reduced rate of butyrate oxidation compared with the control group (194 (81-321) versus 567 (262-894) pmol micrograms-1 h-1, P < 0.05). Normal terminal ileal mucosa oxidized butyrate in greater quantities than glucose and glutamine. Ulcerative colitic terminal ileal mucosa exhibited an impaired rate of butyrate oxidation.

Adolescent↗
PubMed1994

Kinetic resolution of the reaction catalysed by proton-translocating transhydrogenase from Escherichia coli as revealed by experiments with analogues of the nucleotide substrates.

The mechanism, by which transhydrogenase couples transfer of H- equivalents between NAD(H) and NADP(H) to the translocation of protons across a membrane, has been investigated in the solubilised, purified enzyme from Escherichia coli using analogues of the nucleotide substrates. The key observation was that, at low pH and ionic strength, solubilised transhydrogenase catalysed the very rapid reduction of acetylpyridine adenine dinucleotide (an analogue of NAD+) by NADH, but only in the presence of either NADP+ or NADPH. This indicates that the rates of release of NADP+ and NADPH from their binary complexes with the enzyme are slow. The dependences on pH and salt concentration suggest that (a) release of both NADP+ and NADPH are accompanied by the release of H+ from the enzyme and (b) increased ionic strength decreases the value of the pKa of the group responsible for H+ release. Modification of the enzyme with N,N1-dicyclohexylcarbodiimide led to inhibition of the rate of release of NADP+ and NADPH from the enzyme, but had a much smaller effect on the binding and release of NAD+, NADH and their analogues and on the interconversion of the ternary complexes of the enzyme with its substrates. It is considered that the binding and release of H+, which accompany the binding and release of NADP+/NADPH, might be central to the mechanism of proton translocation by the enzyme in its membrane-bound state.

Binding Sites↗
PubMed1994

Duplication of inferior vena cava: its importance in retroperitoneal surgery.

Anomalies of the inferior vena cava arise infrequently. Knowledge of their presence can be established preoperatively with a variety of radiologic studies. This knowledge can prevent hemorrhagic complications from occurring during surgery. We present a case report of a patient with renal cell carcinoma and duplication of the inferior vena cava.

Carcinoma, Renal Cell↗
PubMed1994

Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis.

The short chain fatty acids, acetate, propionate, and butyrate are produced by colonic bacterial fermentation of non-starch polysaccharides. Butyrate is the major fuel source for the colonic epithelium and there is evidence to suggest that its oxidation is impaired in ulcerative colitis. Triplicate biopsy specimens were taken at colonoscopy from five regions of the large bowel in 15 sufferers of ulcerative colitis. These patients all had mild or quiescent colitis as assessed by clinical condition, mucosal endoscopic and histological appearance. The rate of oxidation of glucose, glutamine, and butyrate through to carbon dioxide was compared with that in biopsy specimens from 28 patients who had no mucosal abnormality. Butyrate (272 (199-368)) was the preferred fuel source for the colitic mucosa followed by glutamine (33 (24-62)) then glucose (7.2 (5.3-15)) pmol/micrograms/hour; medians and 95% confidence intervals, p < 0.01. There was no regional difference in the rate of utilisation of these metabolites. In the group with colitis the rate of butyrate oxidation to carbon dioxide was significantly impaired compared with that in normal mucosa decreasing from 472 (351-637) pmol/micrograms/hour to 272 (199-368) pmol/micrograms/hour; median and 95% confidence intervals, p = 0.016. The rate of glucose and glutamine utilisation were not significantly different between normal and colitic mucosa. These data confirm that in quiescent ulcerative colitis there is an impairment of butyrate oxidation.

Adult↗
PubMed1993

New technique to measure mucosal metabolism and its use to map substrate utilization in the healthy human large bowel.

A new method of assessing substrate utilization in gastrointestinal mucosal specimens is described. Small human endoscopic biopsy specimens with wet weights ranging between 1.4 and 12.2 mg were used to quantify the oxidation of three metabolic substrates, glucose, glutamine and butyrate, through to carbon dioxide over a 2-h period. The technique proved to be reproducible and capable of distinguishing variations in mucosal metabolism between individuals (P < 0.0001 for each substrate). Results were similar to those obtained previously using human and rat colonocytes. To characterize the metabolism of the healthy large bowel, specimens were obtained from five regions in 15 patients who had a normal colonoscopic examination. The results show that butyrate is the preferred fuel source of large bowel mucosa, followed by glutamine, then glucose (P < 0.01). There was no significant regional variation in utilization of the three substrates between the five regions; with respect to glutamine, this is contrary to previous findings.

Adult↗
PubMed1988

Carotid endarterectomy in a metropolitan community: the early results after 8535 operations.

Several retrospective community surveys have provoked speculation concerning the safety of carotid endarterectomy (CEA) throughout the United States. To address this serious issue, surgical outcome was calculated for 8535 CEAs entered prospectively into a computer registry by 51 trained vascular surgeons in a large metropolitan area from 1973 to 1985. A total of 7480 procedures (88%) were performed for symptomatic lesions and 1055 (12%) were performed for asymptomatic stenosis or ulceration. There were 178 operative strokes (2.1%) and 135 early deaths (1.6%), for a combined morbidity-mortality rate of 3.2%. Fatal events were attributed to cardiac disease in 0.7%, neurologic complications in 0.6%, and other causes in 0.3%. The stroke rate (n = 148; 2.0%) in symptomatic patients was better than that in asymptomatic patients (n = 30; 2.8%) (chi 2 = 5.2; p less than 0.025), but the combined morbidity-mortality rates (2.9% and 3.7%) were not statistically different. The incidence of stroke reported by surgeons who performed more than 5 CEAs annually (1.7%) was statistically superior to the stroke rate (3.4%) among those with less experience (chi 2 = 37.1; p less than 0.0001). Nevertheless, both groups had acceptable results that were consistent with their training and continued interest in vascular surgery.

Aged↗
PubMed1987

The cadmium and lead content of suspended particulate matter emitted from a U.K. refuse incinerator.

Suspended particulate matter (SPM), sampled from the stack of a large refuse incinerator in the U.K., contained markedly elevated levels of Cd (approximately 1600 micrograms g-1) and Pb (approximately 3%). These values were similar to those previously reported for several other incinerators in Europe, but the Pb concentrations were lower than in the SPM from three American incinerators. Calculation of the metal concentration ratio SPM/fly ash for the U.K. incinerator revealed a three-fold enrichment of the two metals on the SPM. Similar ratios were obtained for several other European incinerators; this correspondence in metal partitioning was linked to the use of electrostatic precipitators in these facilities. The SPM metal data obtained in this study were used to estimate atmospheric emissions of 0.5 t Cd year-1 and 11 t Pb year-1 from the incinerator. Extrapolation of the Cd and Pb emission factors derived from this study to the quantity of refuse incinerated in the U.K. results in atmospheric discharges of 6 t Cd year-1 and 115 t Pb year-1. These estimates are in good agreement with those previously reported by an emissions inventory which identified incineration as the single largest source of airborne Cd in the U.K.

Air Pollutants↗