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S R Thomas

Publications and source records attributed to S R Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2000

Increased sputum amino acid concentrations and auxotrophy of Pseudomonas aeruginosa in severe cystic fibrosis lung disease.

BACKGROUND: Pseudomonas aeruginosa may undergo a phenotypic change from the wild (prototrophic) type to an auxotrophic phenotype in the course of respiratory infection in patients with cystic fibrosis. The clinical significance of this is unclear. A study was undertaken to investigate whether the presence of auxotrophs of P aeruginosa in the sputum of patients with cystic fibrosis correlated with severity of respiratory disease, and whether increased sputum concentrations of amino acids were associated with the emergence of these forms. METHODS: Sixty adult patients with cystic fibrosis, colonised by P aeruginosa, were recruited and baseline clinical data including lung function were recorded. Serial sputum samples were obtained before, during, and after infective exacerbations where possible. These samples were used for routine microbiological culture, assessment of auxotrophy of P aeruginosa, measurement of amino acid content, and neutrophil elastase assay. RESULTS: Auxotrophy was common in patients with cystic fibrosis and 20 (33%) had a mean percentage auxotroph count of more than 50% total cfu/ml. The mean percentage auxotroph count was inversely correlated with forced expiratory volume in one second (FEV(1); tau = -0.194, p = 0.031). The median sputum amino acid concentration of the group was 12.5 mmol/l (range 0.13-40.6). The mean amino acid concentration in 33 subjects during infective exacerbations was 18.2 mmol/l (95% CI 15.1 to 21.3) compared with 12.3 mmol/l (95% CI 9.8 to 14.8) when well (p = 0.001). The amino acid content of sputum was inversely correlated with FEV(1) (tau = -0.253, p = 0.005). CONCLUSIONS: P aeruginosa frequently exhibits auxotrophy in patients with cystic fibrosis, particularly in those with severe underlying pulmonary disease. The sputum amino acid content of patients with cystic fibrosis is high during infective exacerbations and correlates with pulmonary disease severity.

Adolescent↗
PubMed2000

Error analysis of classic colonic transit time estimates.

Estimates of colonic transit times (CTT) through the three colonic segments, right colon, left colon, and rectosigmoid, are commonly based on radiopaque markers. For a given segment, CTT is usually calculated from just the number of markers visible in that segment on abdominal X-rays. This procedure is only strictly valid for the theoretical, but unrealistic, case of continuous marker ingestion (i. e., not for a single or once-daily ingestion). CTT was analyzed using the usual estimate of the mean CTT of one marker and also using a new, more realistic estimate based on the kinetic coefficients of a three-compartment colonic model. We directly compared our compartmental approach to classic CTT estimates by double-marker studies in six patients. We also retrospectively studied CTT in 148 healthy control subjects (83 males, 65 females) and 1,309 subjects with functional bowel disorders (irritable bowel syndrome or constipation). Compared with the compartmental estimates, the classic approach systematically underestimates CTT in both populations, i.e., in patients and in healthy control subjects. The relative error could easily reach 100% independent of the site of colonic transit delay. The normal values of total CTT are then 44.3+/-29.3 instead of 30.1+/-23.6 h for males and 68.2+/-54.4 instead of 47.1+/-28.2 h for females.

Adolescent↗
PubMed2000

Inner medullary lactate production and accumulation: a vasa recta model.

Since anaerobic glycolysis yields two lactates for each glucose consumed and since it is reported to be a major source of ATP for inner medullary (IM) cell maintenance, it is a likely source of "external" IM osmoles. It has long been known that such an osmole source could theoretically contribute to the "single-effect" of the urine concentrating mechanism, but there was previously no suggestion of a plausible source. I used numerical simulation to estimate axial gradients of lactate and glucose that might be accumulated by countercurrent recycling in IM vasa recta (IMVR). Based on measurements in other tissues, anaerobic glycolysis (assumed to be independent of diuretic state) was estimated to consume approximately 20% of the glucose delivered to the IM. IM tissue mass and axial distribution of loops and vasa recta were according to reported values for rat and other rodents. Lactate (P(LAC)) and glucose (P(GLU)) permeabilities were varied over a range of plausible values. The model results suggest that P(LAC) of 100 x 10(-5) cm/s (similar to measured permeabilities for other small solutes) is sufficiently high to ensure efficient lactate recycling. By contrast, it was necessary in the model to reduce P(GLU) to a small fraction of this value (1/25th) to avoid papillary glucose depletion by countercurrent shunting. The results predict that IM lactate production could suffice to build a significant steady-state axial lactate gradient in the IM interstitium. Other modeling studies (Jen JF and Stephenson JL. Bull Math Biol 56: 491-514, 1994; and Thomas SR and Wexler AS. Am J Physiol Renal Fluid Electrolyte Physiol 269: F159-F171, 1995) have shown that 20-100 mosmol/kgH(2)O of unspecified external, interstitial, osmolytes could greatly improve IM concentrating ability. The present study gives several plausible scenarios consistent with accumulation of metabolically produced lactate osmoles, although only to the lower end of this range. For example, if 20% of entering glucose is consumed, the model predicts that papillary lactate would attain about 15 mM assuming vasa recta outflow is increased 30% by fluid absorbed from the nephrons and collecting ducts and that this lactate gradient would double if IM blood flow were reduced by one-half, as may occur in antidiuresis. Several experimental tests of the hypothesis are indicated.

Animals↗
PubMed2000

Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype.

STUDY OBJECTIVES: Inducible nitric oxide synthase (iNOS) is upregulated in a number of inflammatory lung conditions, and exhaled nitric oxide (NO) concentration is increased. However, previous studies in children with cystic fibrosis (CF) have shown that exhaled NO is reduced. The purpose of this investigation was to study exhaled NO concentration in adults with CF, and to investigate the effect of CF genotype and respiratory tract infection on this measurement. DESIGN: Exhaled and nasal NO levels were measured in 54 adult CF subjects and 37 healthy nonsmoking age-matched subjects using a chemiluminesence analyzer. Spirometry (FEV(1) and FVC), CF genotype, and bacterial colonization were also recorded. SETTING: This study was conducted at a national CF center. RESULTS: The mean age of patients was 26.9 years, and the mean FEV(1) was 50.5% predicted (range, 17 to 104%). Nasal NO in the CF patients (mean, 520 parts per billion [ppb]; confidence interval [CI], 452 to 588) was significantly lower (p < 0.001) than in control subjects (987 ppb; CI, 959 to 1,015). Exhaled NO was significantly lower (p < 0. 001) in CF patients (5.0 ppb; CI, 4.1 to 6.1) than in control subjects (7.3 ppb; CI, 6.8 to 7.8). FEV(1) did not correlate with nasal or exhaled NO. No association was observed between genotype and NO values or colonization with Pseudomonas aeruginosa. CONCLUSIONS: Despite the airway inflammation that is characteristic of CF, both nasal and exhaled NO were reduced. There was no association with genotype or infection status. As NO has bacteriostatic effects and may augment mucociliary clearance, this observation may be of clinical importance.

Adolescent↗
PubMed1999

A role for reduced coenzyme Q in atherosclerosis?

Substantial evidence implicates oxidative modification of low density lipoprotein (LDL) as an important event contributing to atherogenesis. As a result, the elucidation of the molecular mechanisms by which LDL is oxidized and how such oxidation is prevented by antioxidants has been a significant research focus. Studies on the antioxidation of LDL lipids have focused primarily on alpha-tocopherol (alpha-TOH), biologically and chemically the most active form of vitamin E and quantitatively the major lipid-soluble antioxidant in extracts prepared from human LDL. In addition to alpha-TOH, plasma LDL also contains low levels of ubiquinol-10 (CoQ10H2; the reduced form of coenzyme Q10). Recent studies have shown that in oxidizing plasma lipoproteins alpha-TOH can exhibit anti- or pro-oxidant activities for the lipoprotein's lipids exposed to a vast array of oxidants. This article reviews the molecular action of alpha-TOH in LDL undergoing "mild" radical-initiated lipid peroxidation, and discusses how small levels of CoQ10H2 can represent an efficient antioxidant defence for lipoprotein lipids. We also comment on the levels alpha-TOH, CoQ10H2 and lipid oxidation products in the intima of patients with coronary artery disease and report on preliminary studies examining the effect of coenzyme Q10 supplementation on atherogenesis in apolipoprotein E knockout mice.

Animals↗
PubMed1999

Antioxidant activities and redox regulation of interferon-gamma-induced tryptophan metabolism in human monocytes and macrophages.

This article summarises studies supporting the proposal that induction of L-tryptophan (Trp) degradation along the kynurenine pathway in human monocytes and macrophages by interferon-gamma (IFN gamma) represents a novel extracellular antioxidant defence that acts to prevent inadvertent oxidative damage to host tissue during inflammation. The studies show that formation and release of the aminophenolic antioxidant 3-hydroxyanthranilic acid (3-HAA) is responsible for the ability of IFN gamma-primed human macrophages to inhibit the oxidation of low density lipoprotein (LDL); an event implicated as an important event in atherogenesis. 3-HAA efficiently inhibits LDL oxidation by acting as an aqueous oxidant scavenger and a synergist for LDL-associated vitamin E. Indoleamine 2,3-dioxygenase activity (IDO) is the initial and rate limiting enzyme of Trp degradation along the kynurenine pathway. Nitric oxide inhibits IDO activity in IFN gamma-primed human macrophages and this may represent a physiological regulatory mechanism of the dioxygenase during inflammation.

3-Hydroxyanthranilic Acid↗
PubMed1999

Radiation dosimetry in nuclear medicine.

Radionuclides are used in nuclear medicine in a variety of diagnostic and therapeutic procedures. A knowledge of the radiation dose received by different organs in the body is essential to an evaluation of the risks and benefits of any procedure. In this paper, current methods for internal dosimetry are reviewed, as they are applied in nuclear medicine. Particularly, the Medical Internal Radiation Dose (MIRD) system for dosimetry is explained, and many of its published resources discussed. Available models representing individuals of different age and gender, including those representing the pregnant woman are described; current trends in establishing models for individual patients are also evaluated. The proper design of kinetic studies for establishing radiation doses for radiopharmaceuticals is discussed. An overview of how to use information obtained in a dosimetry study, including that of the effective dose equivalent (ICRP 30) and effective dose (ICRP 60), is given. Current trends and issues in internal dosimetry, including the calculation of patient-specific doses and in the use of small scale and microdosimetry techniques, are also reviewed.

Alpha Particles↗
PubMed1999

Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway.

The heme enzyme indoleamine 2,3-dioxygenase (IDO) oxidizes the pyrrole moiety of L-tryptophan (Trp) and other indoleamines and represents the initial and rate-limiting enzyme of the kynurenine (Kyn) pathway. IDO is a unique enzyme in that it can utilize superoxide anion radical (O2*- ) as both a substrate and a co-factor. The latter role is due to the ability of O2*- to reduce inactive ferric-IDO to the active ferrous form. Nitrogen monoxide (*NO) and H2O2 inhibit the dioxygenase and various inter-relationships between the nitric oxide synthase- and IDO-initiated amino acid degradative pathways exist. Induction of IDO and metabolism of Trp along the Kyn pathway is implicated in a variety of physiological and pathophysiological processes, including anti-microbial and anti-tumor defense, neuropathology, immunoregulation and antioxidant activity. Antioxidant activity may arise from O2*- scavenging by IDO and formation of the potent radical scavengers and Kyn pathway metabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenine. Under certain conditions, these aminophenols and other Kyn pathway metabolites may exhibit pro-oxidant activities. This article reviews findings indicating that redox reactions are involved in the regulation of IDO and Trp metabolism along the Kyn pathway and also participate in the biological activities exhibited by Kyn pathway metabolites.

Animals↗
PubMed1999

MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.

Humans↗
PubMed1999

MIRD Pamphlet No. 14 revised: A dynamic urinary bladder model for radiation dose calculations. Task Group of the MIRD Committee, Society of Nuclear Medicine.

UNLABELLED: The constant-volume urinary bladder model in the standard MIRD Pamphlet No. 5 (Revised) phantom has recognized limitations. Various investigators have developed detailed models incorporating more physiologically realistic features, such as expanding bladder contents and residual volume, and variable urinary input rate, initial volume and first void time. We have reviewed these published models and have developed a new model for calculation of radiation absorbed dose to the urinary bladder wall incorporating these aspects. METHODS: The model consists of a spherical source with variable volume to simulate the bladder contents and a wall represented by a spherical shell of constant volume. The wall thickness varies as the source expands or contracts. The model provides for variable urine entry rate (three different hydration states), initial bladder contents volume, residual volume and first void time. The voiding schedule includes an extended nighttime gap during which the urine entry rate is reduced to one-half the daytime rate. RESULTS: Radiation-absorbed dose estimates have been calculated for the bladder wall surface (including photon and electron components) and at several depths in the wall (electron component) for 2-18F-fluoro-2-deoxy-D-glucose, 99mTc-diethylenetriaminepentaacetic acid (DTPA), 99mTc-HEDP, 99mTc-pertechnetate, 99mTc-red blood cells (RBCs), 99mTc-glucoheptonate, 99mTc-mercaptoacetyltriglicine chelator (MAG3), 99mTc-methylene diphosphonate (MDP), 99mTc-hexamethylpropylene amine oxime (HMPAO), 99mTc-human serum albumin (HSA), 99mTc-MIBI (rest and stress), 123I-/124I-/131I-OIH, 123I/131I-NaI, 125I-iothalamate, 111In-DTPA and 89Sr-SrCl. CONCLUSION: The new model tends to give a higher radiation absorbed dose to the bladder wall surface than the previous models. Large initial bladder volumes and higher rates of urine flow into the bladder result in lower bladder wall dose. The optimal first voiding time is from 40 min to 3 hr postadministration, depending on radiopharmaceutical. The data as presented in tabular and graphic form for each compound provide guidance for establishing radiation absorbed dose reduction protocols.

Humans↗
PubMed1999

Follicular or Hürthle cell neoplasm of the thyroid: can clinical factors be used to predict carcinoma and determine extent of thyroidectomy?

BACKGROUND: Fine-needle aspiration biopsy (FNAB) and frozen section exam are of limited or no value in distinguishing benign and malignant follicular or Hürthle cell neoplasms of the thyroid gland. METHODS: Patients who underwent thyroidectomy for treatment of a follicular or Hürthle cell neoplasm between 1990 and 1998 were identified and evaluated for age, gender, head and neck irradiation, nodule size, and cytologic atypia to determine whether clinical factors were predictive of carcinoma. RESULTS: Of the 352 patients evaluated for nodular thyroid disease, 75 (21%) underwent thyroidectomy after an indeterminate FNAB finding, 66 with follicular and 9 with a Hürthle cell neoplasm. Seventeen (23%) of the patients had carcinoma-follicular variant of papillary (10), follicular (6), and Hürthle cell (1). Carcinoma was diagnosed in 15 of 64 women and 2 of 11 men (P > .05). The mean age was 43 +/- 21 years and 50 +/- 16 years, respectively, in patients with and without carcinoma (P > . 05). Three patients had previous neck irradiation and none had carcinoma. Mean nodule size was 4.2 +/- 2.7 cm and 4.3 +/- 3.5 cm, respectively, in patients with and without carcinoma (P > . 05). Cytologic atypia was present in 8 of 17 patients with carcinoma and 20 of 58 patients without carcinoma (P > .05). CONCLUSIONS: Clinical factors were not helpful in predicting carcinoma in patients with an indeterminate FNAB finding and thus cannot be used to reliably select patients for more extensive thyroidectomy.

Adenocarcinoma↗
PubMed1999

Bilateral trigger thumbs in identical twins.

Bilateral trigger thumbs in 4-year-old identical male twins are reported. To the authors' best knowledge, this is the first true description of this condition in identical twins. All four thumbs were treated by surgical release of the A1 pulley, with good results. The causes proposed for congenital and acquired trigger thumb are discussed, and it is concluded that the cases described here support a genetic predisposition to the condition.

Child, Preschool↗
PubMed1999

The MIRD perspective 1999. Medical Internal Radiation Dose Committee.

The MIRD schema is a general approach for medical internal radiation dosimetry. Although the schema has traditionally been used for organ dosimetry, it is also applicable to dosimetry at the suborgan, voxel, multicellular and cellular levels. The MIRD pamphlets that follow in this issue and in coming issues, as well as the recent monograph on cellular dosimetry, demonstrate the flexibility of this approach. Furthermore, these pamphlets provide new tools for radionuclide dosimetry applications, including the dynamic bladder model, S values for small structures within the brain (i.e., suborgan dosimetry), voxel S values for constructing three-dimensional dose distributions and dose-volume histograms and techniques for acquiring quantitative distribution and pharmacokinetic data.

Humans↗
PubMed1999

MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee.

The availability of quantitative three-dimensional in vivo data on radionuclide distributions within the body makes it possible to calculate the corresponding nonuniform distribution of radiation absorbed dose in body organs and tissues. This pamphlet emphasizes the utility of the MIRD schema for such calculations through the use of radionuclide S values defined at the voxel level. The use of both dose point-kernels and Monte Carlo simulation methods is also discussed. PET and SPECT imaging can provide quantitative activity data in voxels of several millimeters on edge. For smaller voxel sizes, accurate data cannot be obtained using present imaging technology. For submillimeter dimensions, autoradiographic methods may be used when tissues are obtained through biopsy or autopsy. Sample S value tabulations for five radionuclides within cubical voxels of 3 mm and 6 mm on edge are given in the appendices to this pamphlet. These S values may be used to construct three-dimensional dose profiles for nonuniform distributions of radioactivity encountered in therapeutic and diagnostic nuclear medicine. Data are also tabulated for 131I in 0.1-mm voxels for use in autoradiography. Two examples illustrating the use of voxel S values are given, followed by a discussion of the use of three-dimensional dose distributions in understanding and predicting biologic response.

Animals↗
PubMed1998

Methicillin-resistant Staphylococcus aureus: impact at a national cystic fibrosis centre.

In many patient populations there has been a progressive increase in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA). We examined the prevalence and consequences of acquiring MRSA in the adult cystic fibrosis (CF) population at Royal Brompton. Patients who became colonized by MRSA between 1965 and 1997 were identified from an existing database and case-notes were reviewed. Clinical and microbiological data were recorded. Twenty-six patients became colonized with MRSA during this period. Median age at acquisition was 23.4 years (range 11.8-43.3 years) and median FEV1 (percent predicted) was 28.9% (range 12-81%). Twenty patients (77%) had an FEV1 of < or = 40% predicted MRSA was probably acquired by four patients at Royal Brompton. In 17 patients isolates wer first identified whilst under the care of a total of 11 other institutions. Since the first case of MRSA infection in 1982, there has been an increase in prevalence to a current rate of nine cases in the first seven months of 1997. The commonest site of colonization was the lower airway (96%); the nose (23%) and skin sites (15%) were more rarely affected. Duration of colonization was frequently brief with nine cases (35%) lasting less than one month. The identification of MRSA appeared to be of little clinical significance, and did not generally affect outcomes. Only three patients were MRSA positive at the time of death, and in only one of these was MRSA considered a possible contributing factor.

Adolescent↗
PubMed1998

Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite.

As peroxynitrite is implicated as an oxidant for low-density lipoprotein (LDL) in atherogenesis, we investigated this process using reagent peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1, which produces peroxynitrite via generation of NO. and O2.-). LDL oxidation was assessed by the consumption of ubiquinol-10 (CoQ10H2) and alpha-tocopherol (alpha-TOH), the accumulation of cholesteryl ester hydro(pero)xides, the loss of lysine (Lys) and tryptophan (Trp) residues, and the change in relative electrophoretic mobility. Exposure to ONOO- or SIN-1 resulted in rapid (<1 min) and time-dependent oxidation, respectively, of LDL's lipids and protein. Manipulating the alpha-TOH content by in vivo or in vitro means showed that when ONOO- or SIN-1 was used at oxidant-to-LDL ratios of <100:1 the extent of LDL lipid peroxidation increased with increasing initial alpha-TOH content. In contrast, in vivo enrichment with the co-antioxidant CoQ10H2 decreased LDL lipid peroxidation induced by SIN-1. At oxidant-to-LDL ratios of >200:1, alpha-TOH enrichment decreased LDL lipid peroxidation for both SIN-1 and ONOO-. In contrast to lipid peroxidation, altering the alpha-TOH content of LDL did not affect Trp or Lys loss, independent of the amounts of either oxidant added. Aqueous antioxidants inhibited ONOO--induced lipid and protein oxidation with the order of efficacy: 3-hydroxyanthranilate (3-HAA) > urate > ascorbate. With SIN-1, these antioxidants inhibited Trp consumption, while only the co-antioxidants ascorbate and 3-HAA prevented alpha-TOH consumption and lipid peroxidation. Exposure of human plasma to SIN-1 resulted in the loss of ascorbate followed by loss of CoQ10H2 and bilirubin. Lipid peroxidation was inhibited during this period, though proceeded as a radical-chain process after depletion of these antioxidants and in the presence of alpha-TOH and urate. Bicarbonate at physiological concentrations decreased ONOO--induced lipid and protein oxidation, whereas it enhanced SIN-1-induced lipid peroxidation, Trp consumption, and alpha-tocopheroxyl radical formation in LDL. These results indicate an important role for tocopherol-mediated peroxidation and co-antioxidation in peroxynitrite-induced lipoprotein lipid peroxidation, especially when peroxynitrite is formed time-dependently by SIN-1. The studies also highlight differences between ONOO-- and SIN-1-induced LDL oxidation with regards to the effects of bicarbonate, ascorbate, and urate.

Adenosine Triphosphatases↗