Search PubMed⌕ Search

Biomedical subjects

M L Thomas

Publications and source records attributed to M L Thomas.

At least 55 records · Page 3Linked to original sources
PubMed1999

Migraine: a comprehensive review of new treatment options.

Headaches are among the most common complaints reported to health care professionals and are classified by the International Headache Society as migraine, tension-type, or cluster, with additional subtypes. Classification and etiology of headache should be determined after thorough review of the patient's history. Once diagnosed, migraine can be treated by preventive or abortive measures. Recent developments add new options, including availability of drugs for intranasal administration (sumatriptan, dihydroergotamine) and 5-HT1B/1D agonists (rizatriptan, zolmitriptan, naratriptan, eletriptan). Although placebo-controlled trials are available, few comparative clinical trials of these agents have been conducted; however, important pharmacologic, pharmacokinetic, and clinical differences exist among the drugs.

Analgesics, Opioid↗
PubMed1998

The protein tyrosine phosphatase SHP-1 regulates integrin-mediated adhesion of macrophages.

The Src homology 2 domain phosphatase-1 (SHP-1) is a tyrosine phosphatase containing two amino-terminal SH2 domains and is expressed primarily by hematopoietic-derived cells [1]. The viable motheaten (Hcphme-v) mutant mice (mev) suffer from progressive inflammation due to a deficiency of SHP-1 enzyme activity [2,3] and die at 3-4 months of age from macrophage and neutrophil accumulation in the lung [4]. The mechanism by which SHP-1 deficiency leads to inflammation is unknown. We found that macrophages from mev mice adhered and spread to a greater extent than normal macrophages through alpha m beta 2 integrin-mediated contacts. Whereas macrophages deficient in the transmembrane tyrosine phosphatase CD45 (CD45-/-) spontaneously detached from alpha m beta 2 integrin contacts [5], cells deficient in both CD45 and SHP-1 did not. In SHP-1 deficient macrophages there was a 10-15-fold increase in D-3 phospholipid products of phosphatidylinositol (PI) 3-kinase. Concomitantly, there was a 2-5-fold increase in membrane-associated PI 3-kinase activity in mev macrophages relative to normal macrophages. Treatment of macrophages with the PI 3-kinase inhibitors wortmannin or LY294002 resulted in a dramatic detachment of cells, indicating that PI 3-kinase activity is required for adhesion. These data demonstrate that SHP-1 is necessary for detachment from alpha m beta 2 integrin-mediated contacts in primary macrophages and suggest that a defect in this pathway may contribute to inflammatory disease.

Animals↗
PubMed1998

Negative regulation of antigen receptor signaling in lymphocytes.

The negative regulation of antigen receptor signal transduction is essential for the maintenance of thresholds for activation in lymphocytes. CD45 and SHP-1 are tyrosine phosphatases that are important in maintaining the proper level of tyrosine phosphorylation. Regulation of the src family of tyrosine kinases is mediated by the coordinated action of the tyrosine kinase Csk and the tyrosine phosphatase CD45. B cell receptor signaling is negatively regulated by the recruitment of SHP-1 to bind the B cell transmembrane proteins CD22 and FcgammaRIIb1. SHP-1 also functions to negatively regulate T cell receptor signaling by dephosphorylating and inactivating tyrosine kinases.

Animals↗
PubMed1998

Quality of life and psychosocial adjustment in patients with myelodysplastic syndromes.

Health-related quality of life (QOL) is a dynamic, subjective, multidimensional concept. In chronic illnesses such as myelodysplastic syndromes (MDS), management typically focuses on control of the disease and its symptoms. Yet an equally important consideration is maintaining the patient's QOL. Much research remains to be done on the subject of QOL in the MDS population. MDS patients have unique problems that can affect QOL: they tend to be elderly and to have comorbid conditions; they develop complications resulting from cytopenias such as infection and bleeding; they experience fatigue; they run the risk of converting to a form of acute leukemia typically resistant to therapy; and they face uncertainty. This paper will address the above problems using a conceptual approach to QOL that has been useful for patients with cancer and various chronic illnesses. The approach, based on the work of Ferrell and Cella, concentrates on five areas of the patient's life: the physical, functional, emotional, social, and spiritual. Actual testing of this conceptual framework in the MDS patient population has begun. Here methods of systematically testing and assessing QOL are discussed in order to help clinicians meet the primary purpose of therapy in the setting of chronic illness: improving or preserving the individual's QOL.

Adaptation, Psychological↗
PubMed1998

Maternal temperature during labour using low-dose (ambulatory) epidural analgesia with bupivacaine and fentanyl.

Maternal temperature is known to increase during labour with conventional epidural analgesia mixtures. To date, the effect of newer low-dose (ambulatory) epidural concentrations on maternal temperature has not been studied. Twenty-six women in established labour received epidural analgesia with 0.1% bupivacaine and 2 microg/ml fentanyl. Tympanic membrane (core) temperature was measured every 30 min during labour. There was no significant overall rise in maternal temperature during labour with the use of an ambulatory epidural mixture. One patient exhibited an increase in temperature of 0.8 degrees C to 38 degrees C after 720 min and another of 1.1 degrees C to 38.1 degrees C after 630 min. We conclude that, whilst overall maternal temperature does not increase following low-dose epidural analgesia, individual increases may still occur after 10 h.

Journal Article↗
PubMed1998

'When the talking starts': a framework for analysing tutorials.

The drive towards learner-centred learning which will equip doctors for the next century has encouraged the exploration of alternative ways of learning. A fundamental assumption is that a new learning strategy will either fit into existing patterns or trigger changes in the way that teachers and learners talk together. Despite the use of videotaped tutorials within re-accreditation visits in parts of the UK, the literature reveals no currently existing frameworks to analyse these teaching/learning interactions in the general practice setting. In this qualitative study of tutorials in general practice vocational training, a new grounded theory was developed. This study was innovative in its use of audiotaped tutorials as opposed to espoused theories of interaction. The new theoretical framework of Trainer/GP Registrar interactions consists of five categories: 'gaps to be filled', 'listening in', 'quick fix', 'problem solving' and 'talk on'. Each category illustrates whose agenda was met, who triggers the learning issue, time factors, the educational philosophy and the degree of reflection encouraged. The key principle underpinning this framework is that for learning to be effective a range of educational transactions may need to occur. If educational transactions occur exclusively around one point on the framework, the quality of training and opportunities for critical reflection may suffer. This framework may have implications for the analysis by Trainers of their teaching dialogues in the same way that consultation analysis has informed the development of consultation styles in general practice.

Career Choice↗
PubMed1998

Portfolio learning in general practice vocational training--does it work?

Reflective learning has been widely addressed as an important learning mechanism in the educational literature. The creation of portfolios has been seen as a mechanism to promote this, though there has been little exploration of the place of a portfolio in general practice training. This study examined the introduction of a model of a portfolio learning strategy into one training region. The model had been developed by previous pilot work. The study explored the model in terms of its usefulness in general practice training and its relationship to reflective learning. An educational facilitator was used to support this introduction. Workshops and written material were developed to disseminate and refine ideas generated in the pilot study. This was followed by visits to trainer/general practice registrar (GPR) pairs over a 2-year period. These visits included semistructured interviews, which were tape-recorded and analysed using qualitative methods. Additional written resources, video and audio material as well as new workshops were designed with the researched participants in order to promote the development of the concepts of portfolio learning. Sixty interviews were carried out over a 2-year period with 44 pairs of trainers and GPRs. This included a total of 27 trainers and 44 registrars. Eighteen pairs were interviewed twice. Two focus groups were used at the end of the project. Portfolios have a place to play in general practice vocational training. They act as a bridge between hospital and general practice. They can be used to develop a learner-centred curriculum, explore difficult emotive concerns and facilitate feedback. They do not suit all learning styles. Their use is determined by a cost-benefit analysis described in this study.

Education, Medical, Graduate↗
PubMed1998

The anaesthetic management of a case of Kawasaki's disease (mucocutaneous lymph node syndrome) and Beckwith-Weidemann syndrome presenting with a bleeding tongue.

An unusual case of a 13-month-old child with Kawasaki's disease and the Beckwith-Weidemann syndrome is presented. The child, while anticoagulated with warfarin and aspirin to prevent extension of a coronary artery thrombus, fell and lacerated the tongue resulting in haemorrhage and significant swelling. The ongoing haemorrhage, combined with difficulty in securing venous access resulted in the child becoming shocked. Surgical intervention was required to stem the haemorrhage. The anaesthetic management of a shocked child with a coronary artery aneurysm and thrombosis, a potentially difficult airway and a full stomach is described.

Accidental Falls↗
PubMed1998

Definition of family of coronin-related proteins conserved between humans and mice: close genetic linkage between coronin-2 and CD45-associated protein.

Cell adhesion and signal transduction are coordinated processes that may be linked through regulatory elements such as actin-binding proteins. One such protein that may fulfill this role is coronin. In Dictyostelium discoideum, coronin is involved in cellular processes such as mitosis, cell motility, and phagocytosis. In addition, a human coronin, p57, has been described which interacts with the p47 component of phox proteins and may be involved in the formation of phagocytic vacuoles. Here, we describe a family of four mouse proteins which share 38% identity with Dictyostelium coronin and thus are designated coronin-1, -2, -3, and -4. The gene for coronin-2 is localized to mouse chromosome 19, 5' of the gene for CD45-associated protein. All the coronin proteins contain five highly conserved WD domains. However, their carboxyl regions are quite distinct. Three of the four proteins are ubiquitously expressed, whereas coronin-1, the mouse ortholog of p57, demonstrates expression restricted to hematopoietic cells. Comparison of expressed sequence tag cDNAs indicates that coronin-1, -2, -3, and -4 are highly conserved between mice and humans.

Amino Acid Sequence↗
PubMed1998

Impact of anemia and fatigue on quality of life in cancer patients: a brief review.

Anemia is a frequent complication of cancer and its treatment. Cancer-related anemia is a phenomenon whose physiologic mechanisms are well documented. Yet the impact of that anemia on the individual with cancer is not well understood. This paper describes the impact of anemia, and its distressing manifestations, particularly fatigue, on an individual's quality of life.

Anemia↗
PubMed1997

The association of atopy with a gain-of-function mutation in the alpha subunit of the interleukin-4 receptor.

BACKGROUND: Atopic diseases are very common, and atopy has a strong genetic predisposition. METHODS: Using single-strand conformation polymorphism analysis and DNA sequencing, we searched for mutations in the a subunit of the interleukin-4 receptor that would predispose persons to atopy. We examined the prevalence of the alleles among patients with allergic inflammatory disorders and among 50 prospectively recruited adults. Subjects with atopy were identified on the basis of an elevated serum IgE level (> or = 95 IU per milliliter) or a positive radioimmunosorbent test in response to standard inhalant allergens. The signaling function of mutant interleukin-4 receptor a was examined by flow cytometry, binding assays, and immunoblotting. RESULTS: A novel interleukin-4 receptor alpha allele was identified in which guanine was substituted for adenine at nucleotide 1902, causing a change from glutamine to arginine at position 576 (R576) in the cytoplasmic domain of the interleukin-4 receptor alpha protein. The R576 allele was common among patients with allergic inflammatory disorders (found in 3 of 3 patients with the hyper-IgE syndrome and 4 of 7 patients with severe atopic dermatitis) and among the 50 prospectively recruited adults (found in 13 of 20 subjects with atopy and 5 of 30 without atopy; P=0.001; relative risk of atopy among those with a mutant allele, 9.3). The R576 allele was associated with higher levels of expression of CD23 by interleukin-4 than the wild-type allele. This enhanced signaling was associated with a change in the binding specificity of the adjacent tyrosine residue at position 575 to signal-transducing molecules. CONCLUSIONS: The R576 allele of interleukin-4 receptor alpha is strongly associated with atopy. This mutation may predispose persons to allergic diseases by altering the signaling function of the receptor.

Adult↗
PubMed1997

Alterations of DNA methylation by glutathione depletion.

One of the most consistent findings in cancer cells is an overall decrease of 5-methylcytosine content in DNA. The causes that lead to this alteration are not known. We have shown in a recent study that the methyl-donor, methionine (Met), can easily be depleted and that O- and S-methylation can be impaired in response to glutathione (GSH) depletion. This is because mammalian cells are capable of resynthesizing GSH after GSH is depleted, and GSH turnover occurs at the expense of Met. An extensive utilization of Met for the resynthesis of GSH causes Met depletion and impairment in methylation. In the present study we now demonstrate that GSH depletion has a significant impact on DNA methylation. An i.p. dose of a model GSH-depleting hepatotoxin, bromobenzene (BB), caused a progressive impairment in genomic DNA methylation in the Syrian hamster. The administration of a single i.p. dose of Met labeled with [14CH3]Met to BB-treated hamsters at either 1, 3, 5.5 or 9 h after BB resulted in an increase of methyl-group incorporation into liver genomic DNA at 24 h after BB. With respect to the time points chosen for Met administration, methyl-group incorporation found in the BB + Met groups were 1-, 2-, 4- and 12-fold of the controls that received only Met. We further employed an in vitro methylation assay using specific bacterial SssI CpG methylase as the catalyzing enzyme to demonstrate that BB caused a progressive increase of unmethylated CpG sites in genomic DNA. Interestingly, the time response curve of global DNA methylation in vitro showed an identical pattern to that observed in the in vivo experiment. The results provide strong evidence that GSH-depleting agents significantly impair cytosine methylation. Thus, alterations in gene expression could result from a high dose and/or prolonged exposure to GSH-depleting agents, e.g. medications, chemotherapeutic agents and environmental toxins.

Animals↗
PubMed1997

Retinoids differentially regulate the proliferation of colon cancer cell lines.

In this study, the proliferative effects of retinoids were examined in the MC-26 and LoVo colon adenocarcinoma cell lines. The proliferation of the LoVo cell line was not altered in the presence of the retinoids all trans-retinoic acid (atRA) and 9-cis-retinoic acid (9-cis-RA). Both retinoids, however, stimulated the growth, as measured by cell proliferation, of MC-26 cells. atRA and 9-cis-RA were equipotent in increasing MC-26 cell proliferation, suggesting that the growth stimulation is mediated by one or more retinoic acid receptors (RARs). To determine the RAR which might be responsible for this growth stimulatory effect, we characterized the RAR subtypes which were present in both cell lines. mRNA for the RAR alpha, RAR beta, and RAR gamma were detected in the MC-26 cell. Of the RARs present in MC-26 cells, the RAR alpha does not mediate the growth stimulatory effects of retinoids, for a selective RAR alpha antagonist was unable to prevent the retinoid-induced increase in MC-26 cell growth. RAR alpha, RAR beta, and RAR gamma mRNA are also expressed in the LoVo cell line; the lack of growth-stimulation by retinoids in LoVo cells, therefore, does not seem to be due to the absence of RARs. The results obtained in these experiments demonstrate that the growth response elicited by retinoids can vary between colon cancer cells and that the differences in response may not be solely determined by the RAR subtypes which are expressed in a colon cancer cell line.

Adenocarcinoma↗
PubMed1997

Definition of amino acids sufficient for plasma membrane association of CD45 and CD45-associated protein.

The transmembrane protein tyrosine phosphatase CD45 functions to activate Src-family member kinase activity in T lymphocytes. The inability to activate p56(lck) in CD45-deficient cells results in a higher threshold of signaling through the T cell receptor. The lymphoid-specific CD45-associated protein, CD45AP, interacts with CD45 through transmembrane interactions. Cells lines and mice deficient in CD45 express CD45AP mRNA, yet the protein is poorly expressed, indicating that CD45 is required for efficient expression of CD45AP. Pulse-chase analysis indicates that CD45 associates with CD45AP within minutes of biosynthesis. Cell surface labeling and coimmunoprecipitation demonstrate that CD45AP associates with surface-expressed CD45. Therefore, CD45AP is localized to the plasma membrane. To further characterize this interaction, chimeric proteins containing mutations in CD45 transmembrane regions were expressed, and their ability to associate with CD45AP was determined. Alanine-scan mutations of the CD45 transmembrane region demonstrate that no single amino acid is essential for the interaction with CD45AP. However, the expression of chimeric transmembrane regions indicates that a minimum of three and a maximum of eight amino acids in this region are sufficient to allow interaction with CD45AP.

Amino Acid Sequence↗
PubMed1997

Glutathione depletion-induced thymidylate insufficiency for DNA repair synthesis.

Dietary methionine (Met) deficiency is known to divert folate away from de novo biosyntheses of purines and the pyrimidine, thymidylate, to the resynthesis of Met resulting in deoxynucleoside triphosphate imbalance. We have recently shown that Met can easily be depleted and methylation can be impaired by exposure to a model glutathione (GSH)-depleting agent, bromobenzene (BB). GSH depletion-induced Met depletion, therefore, could cause thymidylate insufficiency for DNA repair synthesis. The administration of thymidine (Thy) should repair this impairment. When this hypothesis was examined in the present study, several interesting results were found. The administration of Thy labeled with [2-14C]Thy to BB-treated Syrian hamsters at either 1, 5, 7 or 9 h after BB resulted in an attenuation of liver toxicity. Intrahepatic hemorrhage, which is a typical characteristic of BB toxicity in the Syrian hamster, was decreased in the BB + Thy groups. The attenuation of liver toxicity was accompanied by a progressive increase of Thy incorporation into liver genomic DNA at 24 h after BB. With respect to the time points chosen for Thy administration, Thy incorporation found in the BB + Thy groups were 2-, 2-, 3- and 4-fold of the controls that received only Thy. The results provide evidence that BB causes a progressive increase of thymidylate insufficiency in liver cells. Thymidylate insufficiency is due to Met depletion, a depletion that occurs as a result of GSH depletion.

Animals↗
PubMed1997

Recent advances in lymphocyte signaling and regulation.

The antigen receptor signaling pathway in lymphocytes is vital to their development and biological function. Recent studies have shown that protein tyrosine kinases and phosphatases are essential components in this receptor signaling pathway and therefore, are critical for the development of mature and functionally competent lymphocytes. The Src kinase family of protein tyrosine kinases coordinates the early signaling events in antigen receptor signaling via phosphorylation of tyrosine-based substrates. These kinases are regulated by the concerted action of the Csk family of non-receptor protein tyrosine kinases and the protein tyrosine phosphatase, CD45. A complex set of phosphorylation and dephosphorylation events regulate protein tyrosine kinase activity. Upon antigen stimulation, Src protein tyrosine kinases in conjunction with the tyrosine kinases, ZAP-70 and Syk initiate downstream effectors leading to Ca2+ mobilization, the activation of the Ras pathway and transcriptional activation. The roles of the various adapter proteins in these pathways are now being elucidated. It is apparent that a network of phosphorylation events connect the antigen receptor to intracellular signaling pathways.

Leukocyte Common Antigens↗
PubMed1997

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.

Animals↗