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Biomedical subjects

C Thomas

Publications and source records attributed to C Thomas.

At least 163 records · Page 9Linked to original sources

Human thrombopoietin structure-function relationships: identification of functionally important residues.

Thrombopoietin (TPO) is a haematopoietic growth factor responsible for megakaryocyte progenitor proliferation and differentiation. It belongs to the four-helix-bundle cytokine family and exerts its biological effects through binding to a specific receptor, c-Mpl. With the use of site-directed mutagenesis we have generated 20 TPO mutants. Each of the TPO mutants was produced in a eukaryotic expression system and the mutants' ability to induce the proliferation of factor-dependent c-Mpl-expressing megakaryoblastic M-O7e cells was compared with that of wild-type TPO. Among the mutations studied, 10 lead to a significant decrease in TPO bioactivity. Of these ten residues, three are located in helix A of the protein (Arg10, Lys14 and Arg17) and four in helix D (His133, Gln132, Lys138 and Phe141), indicating that in TPO, as in other cytokines, these two helices are important for functional cytokine/receptor interactions. Surprisingly, mutant Arg10-->Ala (R10A) lacked any proliferative activity, despite the fact that this mutation was recently reported to have no effect on TPO/c-Mpl binding in a TPO phage ELISA [Pearce, Potts, Presta, Bald, Fendly and Wells (1997) J. Biol. Chem. 272, 20595-20602]. The lack of M-O7e proliferation is probably due to an inability of R10A mutant to promote receptor dimerization and thus receptor activation. Moreover we found that the Arg10 and Arg17 residues of TPO seem to be specific determinants for TPO/c-Mpl recognition. We also demonstrate that the O-glycosylation site located at position 110 of TPO is not necessary for the bioactivity of the cytokine.

Amino Acid Sequence↗

Outcomes of acute exacerbation of severe congestive heart failure: quality of life, resource use, and survival. SUPPORT Investigators. The Study to Understand Prognosis and Preferences for Outcomes and Risks of Treatments.

BACKGROUND: Congestive heart failure (CHF) is a common disease with high health care costs and high mortality rates. Knowledge of the health-related quality of life outcomes of CHF may guide decision making and be useful in assessing new therapies for this population. METHODS: A prospective cohort study was conducted involving 1390 adult patients hospitalized with an acute exacerbation of severe CHF (New York Heart Association class III-IV). Demographic data and health-related quality of life were determined by interview; physiologic status and cost and intensity of care were determined from hospital charts. RESULTS: The median (25th, 75th percentiles) age of patients was 68.0 (58.2, 76.9) years; 61.7% were male. Survival was 93.4% at discharge from the index hospitalization, 72.9% at 180 days, and 61.5% at 1 year. Of patients interviewed at 180 days, the median health rating on a scale of 0 to 100 (0 indicates death; 100, excellent health) was 60 (interquartile range, 50-80), and 59.7% were independent in their activities of daily living. Overall quality of life was reported to be good, very good, or excellent in 58.2% at 180 days. Patients with worse functional capacity were more likely to die. Health perceptions among the patients with available interview data improved at 60 and 180 days after acute exacerbation of severe CHF. CONCLUSIONS: Patients hospitalized for acute exacerbation of severe CHF have a generally poor 6-month survival, but survivors retain relatively good functional status and have good health perceptions. Furthermore, health perceptions improve after the acute exacerbation.

Acute Disease↗

Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease.

The overall peroxidation activity in brain tissue by region from patients with Alzheimer's disease (AD) and age-matched controls was determined employing the thiobarbituric acid-reactive substances (TBARS) assay, a measure of lipid peroxidation, followed by a determination the activities of the antioxidant enzymes Cu/Zn superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), in the frontal, temporal, and cerebellar cortex of 10 AD and 9 control brains. The level of TBARS was elevated in all regions, with particular statistical significance in the temporal cortex when compared to age-matched controls. SOD activity was significantly decreased in AD frontal and AD temporal cortex, while catalase activity was significantly decreased in AD temporal cortex. There was no significant difference in GSH-Px activity found in any of the regions examined. This study supports the theory that in AD the brain is affected by increased oxidative stress which, when combined with a decrease in SOD activity, produces oxidative alterations, seen most significantly in temporal cortex in AD, where the pathophysiologic changes are most severe.

Acatalasia↗

Endoscopic vein harvest for coronary artery bypass grafting: technique and outcomes.

BACKGROUND: The greater saphenous vein is a common conduit for coronary revascularizations. Traditional vein harvesting uses long incision(s) that can lead to significant morbidities. A minimally invasive technique has been developed that allows the harvest of much of the saphenous vein with one incision and fewer morbidities. METHODS: Our technique and outcomes on 110 patients with minimally invasive harvest (endoscopic vein harvesting) is presented. Comparisons are made with an equivalent retrospective group within the same hospital and to a smaller (n = 28) prospective group at other hospitals. RESULTS: Endoscopic vein harvesting has evolved to one above-knee incision of 3 cm length that allows for the harvest of 35 cm of vein. Harvest times were longer for endoscopic vein harvesting, showed a learning curve, and appeared to reach a baseline of 35 minutes. Incision closure times were less for the endoscopic vein harvesting group. Total skin to skin operating times for the entire cardiovascular procedure did not differ between the groups. In relatively homogeneous populations, leg infection rates did not differ, but other leg morbidities were less for the patients who underwent endoscopic vein harvesting. Hospital readmissions for leg wound care were low in both groups although the number of office visits required for leg care was higher for patients undergoing traditional vein harvesting. Pain perception by the patients was much less for the endoscopic vein harvesting and remained lower for up to 4 weeks. CONCLUSIONS: Although endoscopic vein harvesting is a relatively new procedure, it is safe, effective, and less painful for the patient and carries fewer morbidities.

Coronary Artery Bypass↗

Bannayan-Zonana syndrome: a rare autosomal dominant syndrome with multiple lipomas and hemangiomas: a case report and review of literature.

BACKGROUND: Bannayan-Zonana syndrome is a rare hamartomatous disorder, characterized by macrocephaly, multiple lipomas, and hemangiomas. Inheritance is by autosomal dominant transmission with few reported sporadic cases. Male predominance is also reported. METHODS: We describe a patient who presented with multiple subcutaneous lipomas, mild macrocephaly, and an extradural spinal hemangioma. Other affected family members and 24 other previously reported cases are discussed. RESULTS: Spinal hemangiomas have not been described previously with this syndrome. The patient also had a "malignant bone tumor" removed from his humerus 20 years ago. Two of the patient's siblings also had lymphoma, which is an unusual accompaniment not reported previously. Only the male members in the family showed multiple subcutaneous lipomas. CONCLUSION: Some patients with Bannayan-Zonana syndrome may have hamartomatous lesions producing cord compression or intracerebral hemorrhage, or they may rarely have other malignant tumors; therefore it is important that neurosurgeons are aware of the entity. The early diagnosis of BZS is also important for genetic counseling.

Adult↗

Preclinical development of camptothecin derivatives and clinical trials in pediatric oncology.

Although the prognosis of childhood cancers has dramatically improved over the last three decades, new active drugs are needed. Camptothecins represent a very attractive new class of anticancer drugs to develop in paediatric oncology. The preclinical and clinical development of two of these DNA-topoisomerase I inhibitors, i.e. topotecan and irinotecan, is ongoing in paediatric malignancies. Here we review the currently available results of this evaluation. Topotecan proved to be active against several paediatric tumour xenografts. In paediatric phase I studies exploring several administration schedules, myelosuppression was dose-limiting. The preliminary results of topotecan evaluation in phase II study showed antitumour activity in neuroblastoma (response rate: 15% at relapse and 37% in newly diagnosed patients with disseminated disease) and in metastatic rhabdomyosarcoma (40% in untreated patients). Topotecan-containing drug combinations are currently investigated. Irinotecan displayed a broad spectrum of activity in paediatric solid tumour xenografts, including rhabdo-myosarcoma, neuroblastoma, peripheral primitive neuroectodermal tumour, medulloblastoma, ependymoma, malignant glioma and juvenile colon cancer. For several of these histology types, tumour-free survivors have been observed among animals bearing an advanced-stage tumour at time of treatment. The clinical evaluation of irinotecan in children is ongoing. Irinotecan undergoes a complex in vivo biotransformation involving several enzyme systems, such as carboxylesterase, UDPGT and cytochrome P450, in children as well as in adults. Preclinical studies of both drugs have shown that their activity was schedule-dependent. The optimal schedule of administration is an issue that needs to be addressed in children. In conclusion, the preliminary results of the paediatric evaluation of camptothecin derivatives show very encouraging results in childhood malignancies. The potential place of camptothecins in the treatment of paediatric malignant tumours is discussed.

Animals↗

A profile of methicillin resistant Staphylococcus aureus infection in the burn center of the Sultanate of Oman.

A retrospective study of patterns of infection in 168 patients admitted during 1995 and 1996 in the burns-unit of Khoula hospital at Muscat, Oman was performed. Out of 819 isolates positive for pathogenic bacterial culture, there were 326 (39.8%) isolates positive for methicillin resistant Staphylococcus aureus (MRSA) infection. Incidence of MRSA infection was marginally more than that of Pseudomonas aeroginosa. The proportion of patients developing MRSA infection sometime or the other during their burns-unit stay ranging from 1 to 112 days rose from 48% in 1995 to 52.7% in 1996. No sophisticated tests were done to identify the MRSA strain but study of the antibiograms of each MRSA positive isolate showed very similar patterns of sensitivity to different antibiotics. This suggests the source of infection to be common and in all probability 'noscomial', since all patients acquired MRSA infection in the hospital. The susceptibility of MRSA to ciprofloxacin, cotrimoxazole and fucidin was 76, 51 and 37% of isolates in 1995, and 59, 44 and 26% in 1996 were susceptible to these drugs. Vancomycin was the antibiotic to which most MRSA cultures were susceptible, but partial resistance was reported due to very low susceptibility observed in 1.4% of the isolates in 1995 and 1.1% of the isolates in 1996. The control measures being practiced in the burns-unit of Khoula Hospital, especially mechanical cleaning and chemical disinfection of all surfaces, are discussed in detail. This paper emphasizes the need for preventive measures against MRSA infection in the burns-unit.

Adult↗

Illusions of control, underestimations, and accuracy: a control heuristic explanation.

The illusions of control area is reviewed, and 5 conditions that influence control judgments are identified: skill-related factors, success or failure emphasis, need for the outcome, mood, and the intrusion of reality. It is proposed that individuals use a control heuristic that includes perceptions of intentionality and connection. Judgments of intentionality are based on foreseeability, ability to produce the effect, and valence of the outcome. Judgments of connection are based on the perceived association between the action and the outcome, which includes temporal, shared meaning, and predictive association. Effects of motives to overestimate, underestimate, and have accurate assessments of control are explained, using the concepts of hindsight bias, connection, and counterfactuals. In addition, the relation between the control heuristic and illusory correlation research and applications of the control heuristic to coping with chronic illness are explored.

Humans↗

Mebeverine decreases mass movements and stool frequency in lactulose-induced diarrhoea.

BACKGROUND: In spite of its frequent use in the treatment of irritable bowel disease little is known about mebeverine's mode of action in man. AIM: To examine mebeverine's effect on transit though the gut during lactulose-induced diarrhoea. METHODS: Nine healthy volunteers undertook a two-way randomized crossover study. Diarrhoea was induced using lactulose pre-treatment (20 m t.d.s., 4 days) and subjects received either mebeverine (135 mg t.d.s.) or no treatment. Transit of two enteric-coated capsules containing radiolabelled 8.4 mm tablets and 180-250 microM ion exchange resin were followed using gamma scintigraphy. Stool frequency and symptoms were assessed by diary cards. RESULTS: Mebeverine reduced mean daily stool frequency associated with lactulose ingestion from a median of 2.25 (interquartile range (IQR) 1.75-2.75) to 1.5 (IQR 1.25-2.25) movements. Mebeverine significantly reduced the number of mass movements observed in the colon during the 11 h of the study from 2 (2-2) to 1 (1-2), and the number of retrograde movements from 1 (0-2) to 0 (0-0) (P < 0.05). Mebeverine did not significantly alter the gastric emptying rate of the intact capsule (2.9 (1.9-3.2) to 2.8 (2.6-4.0) h) however it induced a small but significant acceleration in small intestinal transit of the capsule (1.6 (0.8-2.0) h to 1.0 (0.52-1.32) h, P=0.02). CONCLUSION: Mebeverine reduces the diarrhoeal effect of lactulose by decreasing the mass movements induced in the ascending colon. This effect may contribute to its clinical effect in irritable bowel syndrome.

Adolescent↗

All change: cancer services in transition.

The policy and health service background to this discussion are the radical changes in cancer services currently underway in the wake of the Calman-Hine Report and the wider changes ushered in by the NHS and Community Care Act 1990 (UK). Using the changing face of hospice care as the focus, the authors explore some of the potential issues and dilemmas involved in providing supportive care for cancer patients and their families. Three 'themes', or areas of concern, are highlighted: links between services, changing organizational factors, and increasing 'medical imperialism'. Potential benefits and drawbacks of the changing ethos and organizational structures are discussed. Interview data are used as 'triggers' for the presentation of the authors' own reflections on developments in the hospice and cancer services' arenas. The paper draws on interview data collected in the pilot phase of a 3-year study on the psycho-social needs of cancer patients and their informal carers in north-west England. Twenty-nine interviews were conducted with a range of professionals involved in the provision of cancer services in Lancaster and Kendal. In the spirit of 'gathering thoughts' and facilitating debate, a commentary on developments in the hospice sector is offered rather than any firm conclusion.

Health Care Reform↗

Cerebral blood flow and CO2 reactivity in interictal migraineurs: a transcranial Doppler study.

There is still some controversy about alterations in velocity of blood flow and in cerebral vasomotor reactivity of intracranial arteries in migraineurs during the interictal phase. By means of simultaneous bilateral transcranial Doppler ultrasonography we, therefore, assessed intracranial blood flow velocities and cerebrovascular reactivity to carbon dioxide of all three basal brain arteries in 20 migraineurs during the interictal phase and 30 nonheadache-prone control subjects. Mean blood flow velocities were higher in migraineurs than in controls in all three arteries on both sides, with a significant difference (P < 0.05) for the right anterior cerebral artery and middle cerebral artery under basal conditions and for the right posterior cerebral artery during hypercapnia. Similarly, the cerebrovascular reactivity to carbon dioxide was always higher in patients than in controls, with a significant difference for the left anterior and the right middle cerebral arteries (P < 0.05) and the right posterior cerebral artery (P < 0.01). The broad overlap of cerebrovascular blood flow velocities and CO2 reactivities in patients and controls precluded identification of values diagnostic of migraine. Nevertheless, transcranial Doppler ultrasonography offers the opportunity to noninvasively monitor cerebral blood flow parameters and, therefore, represents a valuable tool for vascular research in migraine.

Adult↗

Cerebral fungal infections in the immunocompromised host: a literature review and a new pathogen--Chaetomium atrobrunneum: case report.

OBJECTIVE AND IMPORTANCE: A case of a cerebral abscess, occurring in a patient who had undergone bone marrow transplant, caused by a new pathogen, Chaetomium atrobrunneum, and a review of the literature are presented. Although Aspergillus species are by far the most common fungi found in cerebral abscesses in immunocompromised patients, an increasing number of fungi commonly found in nature but not usually associated with infections in humans have been isolated from cerebral abscesses in these patients. CLINICAL PRESENTATION: A 31-year-old male patient, who had undergone a recent bone marrow transplantation for multiple myeloma, presented 3 months after transplantation with right-sided hemiplegia caused by a left parietal hemorrhagic lesion. INTERVENTION: A biopsy guided by computed tomography showed that the abscess contained the fungus C. atrobrunneum. The final identification of the organism was based on cultures, scanning electron microscopic studies, and consultation with the Fungus Testing Laboratory at the University of Texas Health Science Center, San Antonio, TX. The patient was treated with several antifungal medications but developed uncontrolled cerebral edema, which led to further neurological deterioration and eventual death. CONCLUSION: Cerebral abscesses in the immunocompromised patient may no longer be assumed to be caused solely by Aspergillus species. The literature reveals several rare cases of uncommon fungi found in these abscesses. Only four cases of cerebral infections caused by the genus Chaetomium have been reported. The case presented represents the first time a patient who had undergone a bone marrow transplant with a cerebral abscess was found to be caused by the pathogen C. atrobrunneum.

Adult↗

Primary and secondary control over age-related changes in physical appearance.

Beliefs about appearance-related changes due to aging were used to test the effects of perceived control and secondary control (acceptance) in a sample of 412 young, early-middle-age, and late-middle-age college-educated adults. Mean difference in aging-related appearance control and hypotheses regarding the adaptiveness of primary and secondary control were examined. Primary control over aging-related appearance was lower in older adults and secondary control was higher. In addition, the results indicated support for the Primacy/Back-Up Model that primary perceived control is important at all levels of actual control. Those with stronger beliefs in their primary control were less distressed. Secondary control served a back-up function in that it was related to less distress only for those who had medium or lower beliefs in primary control. The implications of these findings, that primary control may be advantageous even in low-control circumstances, are discussed.

Adult↗

Middle cerebral artery main stem thrombosis in two siblings with familial thrombotic thrombocytopenic purpura.

Idiopathic thrombotic thrombocytopenic purpura (TTP) is frequently complicated by microinfarcts in cerebral cortex and subcortical white matter. We describe two sisters who suffered massive hemispheric infarction due to thrombosis of the middle cerebral artery main stem during exacerbations of TTP. Acute TTP may be associated with intraluminal thrombosis of large-diameter arteries in addition to arterioles and capillaries.

Adult↗

Bcl-2 overexpression is associated with resistance to dexamethasone, but not melphalan, in multiple myeloma cells.

Multiple myeloma (MM) is an incurable disease despite an initial response-rate of >60% with conventional or high-dose chemotherapy. Glucocorticosteroids such as dexamethasone (DEX) and alkylating agents such as melphalan (MEL) are capable of inducing complete responses (CR) in >50% of MM patients, however, resistance to these drugs develop rapidly, in >90% of patients, within 2 years of treatment. The exact mechanism of resistance to these drugs is not known. We investigated the mechanism of resistance to DEX and MEL. In particular, we investigated the role of bcl-2 in development of resistance to these two drugs. We tested the role of bcl-2 by transfecting 2 low bcl-2-expressing myeloma cell lines, ARP-1 and 8226, with a bcl-2 expression vector and compared the effects of DEX and MEL on apoptosis, cell cycle distribution and the levels of proapoptotic (bax) and antiapoptotic (bcl-2, bclx) proteins. The results indicate that the two drugs act by a different mechanism with respect to all the parameters tested. While DEX-induced apoptosis was dependent on the level of bcl-2 expression, MEL-induced apoptosis was independent of bcl-2 levels. Treatment with DEX of the low bcl-2-expressing cells (DEX-sensitive) resulted in a rapid apoptosis from all phases of the cell cycle. In contrast, treatment with MEL blocked the cells in late-S/G2 phase of the cell cycle and caused substantial apoptosis, regardless of bcl-2 expression. Major differences between DEX and MEL were also observed with respect to their effects on the levels of bcl-2 and p53. Whereas DEX induced an early (day 1) downregulation of bcl-2 (only in the cells with low bcl-2), treatment with MEL did not affect bcl-2 levels. The levels of bclx and bax remained unchanged following treatment with either MEL or DEX. These results, taken together, suggest that the two drugs target different cellular components and induce apoptosis by different pathways, and that resistance to DEX is associated with low levels of bcl-2, whereas resistance to MEL is independent of bcl-2, and therefore, in vivo resistance to MEL, observed in MM patients, might involve other mechanisms rather than bcl-2.

Antineoplastic Agents, Alkylating↗

Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells.

Multiple myeloma (MM) is an incurable disease despite an initial response-rate of >60% with conventional or high-dose chemotherapy using glucocorticosteroids (i.e. dexamethasone), or alkylating agents (i.e. melphalan). Although these agents are capable of inducing complete remission (CR) in >50% of MM patients, resistance develops rapidly, in >90% of patients, within 2 years of treatment. Therefore, there is a need for new drugs for the treatment of relapsing and refractory MM patients. Gemcitabine (GEM) is a pyrimidine analog that blocks DNA synthesis, whereas, paclitaxel (TAX) is a mitotic spindle poison that promotes microtubular aggregation. Since it appears that these two drugs have different cellular targets, we examined the effect of each drug individually for several parameters and for possible synergy. We studied the cytotoxic effect of TAX and GEM on MM cells expressing varying levels of the antiapoptotic protein bcl-2, which is overexpressed in the majority of myeloma cell from MM patients. We found that both drugs are cytotoxic by inducing apoptosis, however, the extent of apoptosis with TAX, but not with GEM was dependent on the levels of bcl-2 expression. We further investigated the effect of TAX and GEM on the cell cycle distribution and on the levels of bcl-2. The results indicate that the two drugs have different modes of action with respect to each parameter tested. TAX induced arrest of the cells in the G2/M phase of the cell cycle, regardless of bcl-2 levels, however, apoptosis was induced in mitotic cells expressing relatively low levels of bcl-2. In contrast, GEM caused apoptosis of cells in the S-phase, regardless of level of bcl-2 expression. A major difference between TAX and GEM was in their effects on the levels of bcl-2. Whereas, TAX induced an early downregulation of bcl-2 (only in the cells with relatively low levels of bcl-2), treatment with GEM did not affect bcl-2 levels. The effects of TAX on both the cell cycle and bcl-2 were detected very early (4-8 h) and preceded the onset of apoptosis. GEM and TAX act synergistically, at low doses (IC50 of 0.5 microM for GEM and 0.025 microM for TAX), to effectively kill bcl-2 overexpressing cells that are resistant to higher doses (0.25 microM) of TAX alone. Therefore, we have initiated a phase II clinical trial of TAX and GEM for MM patients refractory to current therapy.

Antimetabolites, Antineoplastic↗

Hematology and chemistry reference values for free-ranging harbor seals (Phoca vitulina) and the effects of hemolysis on chemistry values of captive harbor seals.

Most reported laboratory reference values for harbor seals (Phoca vitulina) are derived from captive seals, or stranded seals that have recovered from disease in marine mammal centers. This study established hematology and serum chemistry reference values for free-ranging harbor seals, using methods and that are current and readily available, and determined the effects of hemolysis on serum chemistry values of captive harbor seals. Blood samples were collected for hematologic and serum chemistry measurements from 14 clinically normal, adult male and female harbor seals and two juvenile harbor seals (approximate age 6 mo) captured in saltwater sloughs and estuaries near Moss Landing, California, USA. Values for amylase, globulin, and differential leukocyte count, not previously reported, were determined. In general, hematology and chemistry values in adults were similar to those reported for free-ranging and captive harbor seals, except for glucose, urea nitrogen, and lactate dehydrogenase (LDH) values, which were higher than those reported previously. Red blood cell counts in the two juveniles were higher than in adults and in young harbor seals studied previously. To determine the effects of hemolysis on serum chemistry values, two intensities of hemolysis were generated experimentally in blood collected from 11 harbor seals recovering from injuries or stranding at the Marine Mammal Center (Sausalito, California 94965, USA). Moderate hemolysis (++, 1 g/L hemoglobin, red-tinged) significantly increased LDH activity, whereas severe hemolysis ( , 2 g/L hemoglobin, cherry red) significantly increased total protein, albumin, calculated globulin, LDH, and total bilirubin and significantly decreased creatinine. The effects of hemolysis must be considered when chemistry results of harbor seals are interpreted.

Animals↗

Molecular, genetic and physiological analysis of Cladosporium resistance gene function in tomato.

Characterization of the DNA sequence of 4 tomato leaf mould disease resistance genes (Cf-2, Cf-4, Cf-5 and Cf-9) leads to the prediction that they encode C-terminally membrane anchored glycopeptides with many extracytoplasmic leucine rich repeats (LRRs). The N terminal LRRs are variable between the Cf-genes, suggesting a role in specificity, and the C terminal LRRs are more conserved, suggesting a role in signal transduction. Genetic analysis has revealed several Rcr genes that are required for Cf-gene function; their isolation will help us understand how Cf-genes work. Cf-9 confers responsiveness to pathogen-encoded Avr9 peptide on introduction to tobacco. Tobacco suspension cultures carrying the Cf-9 gene produce reactive oxygen species in response to Avr9 peptide, whereas untransformed cultures do not. The significance of these observations is discussed.

Cladosporium↗