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Biomedical subjects

A M Cook

Publications and source records attributed to A M Cook.

At least 37 records · Page 2Linked to original sources
PubMed1999

Avascular necrosis in patients treated with BEP chemotherapy for testicular tumours.

Avascular necrosis (AVN) is known to occur after combination chemotherapy for lymphomas and leukaemias that includes high dose corticosteroids, but it has been reported rarely in patients with solid tumours. We describe five recent cases in young men with testicular tumours (three of which were of good prognosis), who had been treated with chemotherapy using dexamethasone as an antiemetic. Dexamethasone is a low cost and effective antiemetic, but it may be responsible for inducing AVN in patients receiving chemotherapy for solid tumours. A prospective survey of the frequency of AVN is justified to quantify the extent of the problem.

Adult↗
PubMed1999

Squamous cell carcinoma of the thyroid: outcome of treatment in 16 patients.

AIMS AND METHODS: Squamous cell carcinoma of the thyroid is very rare and has a poor prognosis. Treatment and outcome were retrospectively analysed in a consecutive series of 16 patients treated at the Royal Marsden Hospital, with the aim of establishing guidelines for management. RESULTS: Twelve of the 16 patients had locoregional disease only at presentation and four had distant metastases. Eight of the 16 underwent surgery and four were given post-operative radiotherapy. Radiotherapy alone was used in six patients unsuitable for surgery. Median survival was 16 months. There were three long-term survivors; each had localized disease treated with surgery and post-operative radiotherapy. Patients treated with surgery alone all developed local recurrence. Two of six patients treated with radiotherapy alone had a partial response but all subsequently developed progressive local disease. Chemotherapy was used in two patients with no response. CONCLUSIONS: Long-term survival is possible if disease is diagnosed early and is completely resected. Surgery should be followed by radical dose radiotherapy.

Adult↗
PubMed1999

Desulfonispora thiosulfatigenes gen. nov., sp. nov., a taurine-fermenting, thiosulfate-producing anaerobic bacterium.

Strain GKNTAUT has been described as a bacterium able to ferment the organosulfonate taurine (2-aminoethanesulfonate) quantitatively to acetate, ammonia and thiosulfate, an unusual metabolic product. This novel fermentation has now also been observed in four independent isolates from two continents. All five organisms were strictly anaerobic, Gram-positive, motile, spore-forming bacteria. Enrichments with isethionate (2-hydroxyethanesulfonate) and cysteate (2-amino-3-sulfopropionate), in contrast, yielded bacteria that disproportionated the sulfonate to sulfate and sulfide. The phylogenetic location of the taurine fermenters was analysed on the basis of 16S rDNA sequences. Strain GKNTAUT (= DSM 11270T = ATCC 700533T) is described as the type strain of a new genus and species, for which the name Desulfonispora thiosulfatigenes gen. nov., sp. nov. is proposed.

Anaerobiosis↗
PubMed1999

Stage IV endometrial carcinoma: a 10 year review of patients.

Stage IV endometrial cancer is uncommon, often occurs in elderly patients and has a poor prognosis, which makes the choice of treatment difficult. 18 patients with stage IV endometrial cancer presenting over a 10 year period, between 1987 and 1997, were reviewed with regard to mode of treatment and response. The mean age was 65 years. Five had disease confined to the pelvis and 13 had extra pelvic disease. 15 of 18 patients had a total abdominal hysterectomy (TAH). One patient received radiotherapy alone and five received post-operative radiotherapy. Overall freedom from pelvic symptoms was achieved in seven of 18 patients. All seven had undergone TAH and two had received post-operative radiotherapy. Progestogens were given to 13 patients. Six received progestogens alone, without radiotherapy or chemotherapy. Of these, two responded, one for 9 months and one with verified lung metastases, who had a complete response, is still alive at 6.5 years. Eight patients received chemotherapy, with single agent cisplatin or carboplatin AUC 6. Three patients responded, one for 4.5 years. The overall median survival was 12 months from diagnosis. Actuarial 5 year survival was 15% (CI 3-36). There was no significant survival difference for, hormone therapy or chemotherapy. Stage IV endometrial cancer has a poor prognosis but durable response can be achieved in some patients.

Adult↗
PubMed1998

Magnetic resonance imaging of the whole spine in suspected malignant spinal cord compression: impact on management.

Patients with suspected malignant spinal cord compression may present with a misleading sensory level or have multiple levels of compression that are not apparent clinically or on imaging of a limited area of the spine. To estimate how often this occurs and to evaluate a policy of magnetic resonance imaging (MRI) of the whole spine for any patient with suspected cord compression, data from 127 patients who had undergone MRI scans of the whole spine were reviewed. In 85 of 127 scans, there was evidence of compression of or impingement upon the spinal cord. A sensory level was present in 47 of these 85 patients, but in 12/47 (26%) the sensory level was four or more segments below or three or more segments above the actual lesion. Multiple levels of compression or impingement were found in 33 of 85 (39%) patients; in 24 of these, more than one region (cervical/thoracic/lumbar) of the cord was involved. For 32 patients who commenced radiotherapy to a treatment volume based on clinical criteria before the MRI scan was available, the radiotherapy fields needed modification in 16 (50%) as a result of the MRI findings. The results support a policy of MRI of the whole spine in any patient with suspected malignant spinal cord compression.

Female↗
PubMed1998

Leucocyte filterability: comparing diluted with undiluted blood.

Red blood cells and about 95% of white blood cells have an immediate and constant effect on the flow of undiluted or diluted blood through 5 microm filters. The remaining 5% of all leucocytes exert an increasing influence on flow such that the rate of flow of diluted and undiluted blood through these filters is continually declining over a period of 150 s. Analysis of this declining flow rate enables these cells to be counted and their rheological properties to be deduced. Approximately 50% of these slow leucocytes pass through the filters with a transit time of about 30 s and the remaining cells act as pore blockers for 150 s. The numbers and flow properties of slow leucocytes was approximately the same in blood from young women (25 years) and older men (65 years). However, the number of slow leucocytes was increased in a group of men (65 years) suffering from peripheral arterial occlusive disease. Dilution of the blood with phosphate-buffered saline increased the numbers of slow leucocytes in both of the older, but not the younger, group of volunteers. This effect was particularly noticeable in the patient group. It is recommended that filtration studies of the rheological profile of leucocytes can, and must, be performed with undiluted blood. The properties after dilution may sometimes, but not invariably, reflect changes ex vivo as well as inherent differences in the cells themselves.

Adult↗
PubMed1998

Microbial desulfonation.

Organosulfonates are widespread compounds, be they natural products of low or high molecular weight, or xenobiotics. Many commonly found compounds are subject to desulfonation, even if it is not certain whether all the corresponding enzymes are widely expressed in nature. Sulfonates require transport systems to cross the cell membrane, but few physiological data and no biochemical data on this topic are available, though the sequences of some of the appropriate genes are known. Desulfonative enzymes in aerobic bacteria are generally regulated by induction, if the sulfonate is serving as a carbon and energy source, or by a global network for sulfur scavenging (sulfate-starvation-induced (SSI) stimulon) if the sulfonate is serving as a source of sulfur. It is unclear whether an SSI regulation is found in anaerobes. The anaerobic bacteria examined can express the degradative enzymes constitutively, if the sulfonate is being utilized as a carbon source, but enzyme induction has also been observed. At least three general mechanisms of desulfonation are recognisable or postulated in the aerobic catabolism of sulfonates: (1) activate the carbon neighboring the C-SO3- bond and release of sulfite assisted by a thiamine pyrophosphate cofactor; (2) destabilize the C-SO3- bond by addition of an oxygen atom to the same carbon, usually directly by oxygenation, and loss of the good leaving group, sulfite; (3) an unidentified, formally reductive reaction. Under SSIS control, different variants of mechanism (2) can be seen. Catabolism of sulfonates by anaerobes was discovered recently, and the degradation of taurine involves mechanism (1). When anaerobes assimilate sulfonate sulfur, there is one common, unknown mechanism to desulfonate the inert aromatic compounds and another to desulfonate inert aliphatic compounds; taurine seems to be desulfonated by mechanism (1).

Alkanesulfonates↗
PubMed1998

Methods for studying leukocyte filterability in undiluted blood from intermittent claudicants.

Leukocytes are characterised from their influence on the filterability of undiluted blood from patients with PAOD (intermittent claudicants - Fontaine Stage II) and a group of sex and age-matched controls. Undiluted blood was filtered through 5 microm Nuclepore (Hemafil) filters for 300 s, at 711 Pa and room temperature, using a custom-made constant pressure filtrometer. Four populations of leukocytes are identified in both groups. In the control group, 94.4% of the leukocytes are identified as fast leukocytes with a transit time of 1.8 s. The remaining white cells are recognised as slow flowing leukocytes and subdivided into three further sub-populations. The first of these (SL1; 2.8% of total leukocyte count) is characterised by a transit time of 31.7 s, a second population (SL2; 1.5% of total leukocyte count) by a transit time of 145.8 s while the remaining cells are identified as pore blockers (PB) under these conditions. A similar rheological classification is valid in the patients but the sum of the three minor populations is elevated compared to controls (p = 0.001) although there is no overall leukocytosis. The only significant difference in flow properties of any blood cells, between the two groups of volunteers, is seen in the major population of leukocytes with an elevated transit time of 2.4 s. Stepwise regression analysis identifies the concentration of fast leukocytes, SL2 and PB as the major variables affecting blood flow through the filter. It is argued that the higher concentration of SL2 and PB probably reflect the increased sensitivity of neutrophils to physical stimuli.

Aged↗
PubMed1997

Thiosulfate as a metabolic product: the bacterial fermentation of taurine.

Thiosulfate (S2O32-) is a natural product that is widely utilized in natural ecosystems as an electron sink or as an electron donor. However, the major biological source(s) of this thiosulfate is unknown. We present the first report that taurine (2-aminoethanesulfonate), the major mammalian solute, is subject to fermentation. This bacterial fermentation was found to be catalyzed by a new isolate, strain GKNTAU, a strictly anaerobic, gram-positive, motile rod that formed subterminal spores. Thiosulfate was a quantitative fermentation product. The other fermentation products were ammonia and acetate, and all could be formed by cell-free extracts.

Acetates↗
PubMed1997

Taurine reduction in anaerobic respiration of Bilophila wadsworthia RZATAU.

Organosulfonates are important natural and man-made compounds, but until recently (T. J. Lie, T. Pitta, E. R. Leadbetter, W. Godchaux III, and J. R. Leadbetter. Arch. Microbiol. 166:204-210, 1996), they were not believed to be dissimilated under anoxic conditions. We also chose to test whether alkane- and arenesulfonates could serve as electron sinks in respiratory metabolism. We generated 60 anoxic enrichment cultures in mineral salts medium which included several potential electron donors and a single organic sulfonate as an electron sink, and we used material from anaerobic digestors in communal sewage works as inocula. None of the four aromatic sulfonates, the three unsubstituted alkanesulfonates, or the N-sulfonate tested gave positive enrichment cultures requiring both the electron donor and electron sink for growth. Nine cultures utilizing the natural products taurine, cysteate, or isethionate were considered positive for growth, and all formed sulfide. Two clearly different pure cultures were examined. Putative Desulfovibrio sp. strain RZACYSA, with lactate as the electron donor, utilized sulfate, aminomethanesulfonate, taurine, isethionate, and cysteate, converting the latter to ammonia, acetate, and sulfide. Strain RZATAU was identified by 16S rDNA analysis as Bilophila wadsworthia. In the presence of, e.g., formate as the electron donor, it utilized, e.g., cysteate and isethionate and converted taurine quantitatively to cell material and products identified as ammonia, acetate, and sulfide. Sulfite and thiosulfate, but not sulfate, were utilized as electron sinks, as was nitrate, when lactate was provided as the electron donor and carbon source. A growth requirement for 1,4-naphthoquinone indicates a menaquinone electron carrier, and the presence of cytochrome c supports the presence of an electron transport chain. Pyruvate-dependent disappearance of taurine from cell extracts, as well as formation of alanine and release of ammonia and acetate, was detected. We suspected that sulfite is an intermediate, and we detected desulfoviridin (sulfite reductase). We thus believe that sulfonate reduction is one aspect of a respiratory system transferring electrons from, e.g., formate to sulfite reductase via an electron transport system which presumably generates a proton gradient across the cell membrane.

Acetates↗
PubMed1997

Conjugative plasmids and the degradation of arylsulfonates in Comamonas testosteroni.

Comamonas testosteroni T-2 degrades p-toluenesulfonate (TSA) via p-sulfobenzoate (PSB) and protocatechuate and degrades toluenecarboxylate via terephthalate (TER) and protocatechuate. The appropriate genes are expressed in at least five regulatory units, some of which are also found in C. testosteroni PSB-4 (F. Junker, R. Kiewitz, and A. M. Cook, J. Bacteriol. 179:919-927, 1997). C. testosteroni T-2 was found to contain two plasmids, pTSA (85 kbp) and pT2T (50 kbp); a TSA- mutant (strain TER-1) contained only plasmid pT2T. C. testosteroni PSB-4, which does not degrade TSA, contained one plasmid, pPSB (85 kbp). The type strain contained no plasmids. Conjugation experiments showed that plasmid pTSA (possibly in conjunction with pT2T) was conjugative, and the single copy of the TSA operon (tsaMBCD) with its putative regulator gene (tsaR) in strain T-2 was found on plasmid pTSA, which also carried the PSB genes (psbAC) and presumably transport for both substrates. Plasmid pTSA was assigned to the IncP1 beta group and was found to carry two copies of insertion element IS1071. Plasmid pPSB (of strain PSB-4), which could be maintained in strains with plasmid pTSA or pT2T, was also conjugative and was found to carry the PSB genes as well as to contain two copies of IS1071. In attempted conjugations with the type strain, no plasmid was recovered, but the PSB+ transconjugant carried two copies of IS1071 in the chromosome. We presume the PSB genes to be located in a composite transposon. The genes encoding the putative TER operon and degradation of protocatechuate, with the meta cleavage pathway, were attributed a chromosomal location in strains T-2 and PSB-4.

Amino Acid Sequence↗
PubMed1997

Characterization of the p-toluenesulfonate operon tsaMBCD and tsaR in Comamonas testosteroni T-2.

Comamonas testosteroni T-2 uses a standard, if seldom examined, attack on an aromatic compound and oxygenates the side chain of p-toluenesulfonate (TS) (or p-toluenecarboxylate) to p-sulfobenzoate (or terephthalate) prior to complete oxidation. The expression of the first three catabolic enzymes in the pathway, the TS methyl-monooxygenase system (comprising reductase B and oxygenase M; TsaMB), p-sulfobenzyl alcohol dehydrogenase (TsaC), and p-sulfobenzaldehyde dehydrogenase (TsaD), is coregulated as regulatory unit R1 (H. R. Schlafli Oppenberg, G. Chen, T. Leisinger, and A. M. Cook, Microbiology [Reading] 141:1891-1899, 1995). The components of the oxygenase system were repurified, and the N-terminal amino acid sequences were confirmed and extended. An internal sequence of TsaM was obtained, and the identity of the [2Fe-2S] Rieske center was confirmed by electron paramagnetic resonance spectroscopy. We purified both dehydrogenases (TsaC and TsaD) and determined their molecular weights and N-terminal amino acid sequences. Oligonucleotides derived from the partial sequences of TsaM were used to identify cloned DNA from strain T-2, and about 6 kb of contiguous cloned DNA was sequenced. Regulatory unit R1 was presumed to represent a four-gene operon (tsaMBCD) which was regulated by the LysR-type regulator, TsaR, encoded by a deduced one-gene transcriptional unit. The genes for the inducible TS transport system were not at this locus. The oxygenase system was confirmed to be a class IA mononuclear iron oxygenase, and class IA can now be seen to have two evolutionary groups, the monooxygenases and the dioxygenases, though the divergence is limited to the oxygenase components. The alcohol dehydrogenase TsaC was confirmed to belong to the short-chain, zinc-independent dehydrogenases, and the aldehyde dehydrogenase TsaD was found to resemble several other aldehyde dehydrogenases. The operon and its putative regulator are compared with units of the TOL plasmid.

Alcohol Dehydrogenase↗
PubMed1996

Comparison of mitozantrone and epirubicin in advanced breast cancer.

Forty chemotherapy naive patients with metastatic or locally advanced breast cancer were treated in a randomized trial comparing mitozantrone 14 mg/m2 with epirubicin 75 mg/m2 given intravenously at 3-weekly intervals. There was a 40% (95% confidence interval (CI) 8-72; P = 0.013) higher partial response rate with epirubicin (11/18) than with mitozantrone (4/19). Epirubicin caused significantly more alopecia (difference 76%; 95% CI 57-96; P < 0.0001) and nausea/vomiting (difference = 38%; 95% CI 10-67; P = 0.01). Three patients who received long courses of epirubicin experienced cardiac failure; two were proved to have cardiomyopathy. The median survival for the epirubicin and mitozantrone groups were 9.5 and 8 months respectively. Thus, although epirubicin gave a higher response rate it also caused more toxicity.

Antineoplastic Agents↗
PubMed1996

Degradative pathways for p-toluenecarboxylate and p-toluenesulfonate and their multicomponent oxygenases in Comamonas testosteroni strains PSB-4 and T-2.

Three multicomponent oxygenases involved in the degradation of p-toluenesulfonate and p-toluenecarboxylate and the regulation of their synthesis have been examined in three strains (T-2, PSB-4 and TER-1) of Comamonas testosteroni. Strain T-2 utilizes p-toluenesulfonate as a source of carbon and energy for growth via p-sulfobenzoate and protocatechuate, and p-toluenecarboxylate via terephthalate and protocatechuate, and has the unusual property of requiring the reductase (TsaB) of the toluenesulfonate methyl monooxygenase system (TsaMB) in an incompletely expressed sulfobenzoate dioxygenase system (PsbAC) [Schläfli Oppenberg, H.R., Chen, G., Leisinger, T. & Cook, A. M. (1995). Microbiology 141, 1891-1899]. The independently isolated C. testosteroni PSB-4 utilized only sulfobenzoate and terephthalate via protocatechuate. Mutant TER-1, derived from strain T-2, utilized only terephthalate via protocatechuate. We detected no enzymes of the pathway from toluenesulfonate to sulfobenzoate in strains PSB-4 and TER-1, and confirmed by PCR and Southern blot analysis that the genes (tsaMB) encoding toluenesulfonate monooxygenase were absent. We concluded that, in strain PSB-4, the regulatory unit encoding the genes for the conversion of toluenesulfonate to sulfobenzoate was missing, and that generation of mutant TER-1 involved deletion of this regulatory unit and of the regulatory unit encoding desulfonation of sulfobenzoate. The degradation of sulfobenzoate in strain PSB-4 was catalysed by a fully inducible sulfobenzoate dioxygenase system (PsbACPSB-4), which, after purification of the oxygenase component (PsbAPSB-4), turned out to be indistinguishable from the corresponding component from strain T-2 (PsbAT-2). Reductase PsbCPSB-4, which we could separate but not purify, was active with oxygenase PsbAPSB-4 and PsbAT-2. Oxygenase PsbAPSB-4 was shown by electron paramagnetic resonance spectroscopy to contain a Rieske [2Fe-2S] centre. The enzyme system oxygenating terephthalate was examined and the oxygenase component purified and characterized. The oxygenase component in strains T-2 (and mutant TER-1) and PSB-4 were indistinguishable. The reductase component, which we separated but failed to purify, was active with the oxygenase from all strains. Gains and losses of blocks of genes in evolution is discussed.

Benzenesulfonates↗
PubMed1996

The assimilation of sulfur from multiple sources and its correlation with expression of the sulfate-starvation-induced stimulon in Pseudomonas putida S-313.

Conditions were optimized for the batch growth of Pseudomonas putida S-313 under sulfur-limited conditions. P. putida grew exponentially with sulfate as the sole source of sulfur, and growth was concomitant with the utilization of sulfate until it was exhausted. A further 20% of protein was synthesized after the apparent disappearance of sulfate. A mass balance for the utilized sulfate in cell material was calculated, given the observed molar growth yield of about 3.6 kg protein (mol S)-1 and a sulfur content of 0.41% S in dry matter. Similar data were obtained for growth with cysteine and thiocyanate. The organism also grew exponentially with 4-toluenesulfonate (TS) as sulfur source, essentially as observed with sulfate, except that negligible protein formation after exhaustion of TS was observed. Similar data were also obtained with 4-nitrocatecholsulfate (NCS) and ethanesulfonate. Any substrate pair selected from sulfate, cysteine and thiocyanate was utilized simultaneously, and although one of the pair of substrates was always preferred, growth continued at the same rate when only one substrate remained. Growth after substrate exhaustion was observed. Any substrate pair selected from TS, NCS and ethanesulfonate gave similar data, but with less growth after exhaustion of the sulfur sources. If a mixed substrate pair was chosen from the two groups, the sulfur source from the first-named group was initially used exclusively, and the second source of sulfur was utilized subsequently, after a lag phase. The data are considered to reflect the control of scavenging for sulfur and of distribution of sulfur in the cell exerted by the sulfate-starvation-induced stimulon.

Culture Media↗
PubMed1996

Anaerobic Desulfonation of 4-Tolylsulfonate and 2-(4-Sulfophenyl) Butyrate by a Clostridium sp.

Alkyl- and arylsulfonates were tested as sole added sources of sulfur for the growth of enrichment cultures under strictly anaerobic denitrifying or fermentative conditions. Cultures that utilized taurine, ethylsulfonate, the dyestuffs orange II and acid red I, tolylsulfonate, 2-(4-sulfophenyl)butyrate (SPB), a dialkyltetralinesulfonate, and 1-(4-sulfophenyl)octane were readily obtained. We chose to work with the simple aromatic compounds and isolated a fermentative bacterium, strain EV4, which utilized SPB as the sole added source of sulfur in glucose-mineral medium. The organism was identified as a Clostridium sp. related to Clostridium beijerinckii. Clostridium sp. strain EV4 utilized seven of seven tested arylsulfonates quantitatively. The growth yield was about 3 kg of protein per mol of sulfur, whether sulfonate or sulfate was utilized. A major product specific to each sulfonate could be observed. Although no product was identified, the existence of anaerobic desulfonation has been established.

Journal Article↗
PubMed1995

Purification and characterization of the arylsulfatase synthesized by Pseudomonas aeruginosa PAO during growth in sulfate-free medium and cloning of the arylsulfatase gene (atsA).

An arylsulfatase (EC 3.1.6.1) was extracted from Pseudomonas aeruginosa PAO1 and purified 2700-fold to homogeneity. Synthesis of this enzyme was repressed when sulfate, cysteine or thiocyanate was supplied as the sole sulfur source for growth, but derepressed with all other sulfur sources tested. The apparent molecular mass was determined by SDS/PAGE to be 57 kDa, and the enzyme was presumed to be a monomer after gel filtration chromatography. The arylsulfatase showed maximal activity at 57 degrees C and pH 8.9, and a Km of 105 microM for 4-nitrocatecholsulfate. Despite previous reports that both inducible and derepressible forms of arylsulfatase exist in P. aeruginosa, we found only one enzyme under a variety of growth conditions: a sulfate-repressed enzyme with a native isoelectric point of 4.76. The gene encoding this enzyme (atsA) was isolated by complementation of a Tn5-751 mutant of P. aeruginosa PAO1. Sequencing revealed a 1602-bp reading frame encoding a 534-amino-acid protein with sequence similarity to known bacterial and eukaryotic arylsulfatases (30-40% and 25-30% identity, respectively), but lacking the signal peptide which is present in all known sequences. The lack of this signal peptide suggests that the P. aeruginosa arylsulfatase is neither periplasmic nor membrane-associated, unlike other known arylsulfatases. The atsA gene was located at 15-17' on the P. aeruginosa genome by Southern hybridization. Only a single copy was observed under moderate stringency conditions.

Amino Acid Sequence↗