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Biomedical subjects

R A Mitchell

Publications and source records attributed to R A Mitchell.

At least 19 recordsLinked to original sources
PubMed2000

Repair of mycotic paravisceral aneurysm with a fenestrated stent-graft.

PURPOSE: To report the successful endovascular repair of a mycotic paravisceral aneurysm using a fenestrated stent-graft. METHODS AND RESULTS: A 55-year-old white female with a history of rheumatoid arthritis presented with an 8-cm paravisceral aneurysm secondary to pneumonia complicated by empyema. Intravascular ultrasound identified a defect in the aortic wall at the level of the celiac axis. Repair was accomplished with a fenestrated stent-graft that excluded the aneurysm and maintained flow to the celiac axis and superior mesenteric artery. Recovery was uneventful and the patient was discharged in 2 days. Six-month follow-up computed tomographic scanning confirmed aneurysm exclusion and flow to the celiac and superior mesenteric arteries. There was no evidence of graft infection. The patient died from a clinically diagnosed myocardial infarction 10 months after the stent-graft repair. CONCLUSIONS: Fenestrated stent-graft repair may evolve into a useful technique for the treatment of mycotic paravisceral aneurysms.

Aneurysm, False↗
PubMed1999

Sustained mitogen-activated protein kinase (MAPK) and cytoplasmic phospholipase A2 activation by macrophage migration inhibitory factor (MIF). Regulatory role in cell proliferation and glucocorticoid action.

Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory mediator with the unique ability to counter-regulate the inhibitory effects of glucocorticoids on immune cell activation. MIF is released from cells in response to glucocorticoids, certain pro-inflammatory stimuli, and mitogens and acts to regulate glucocorticoid action on the ensuing inflammatory response. To gain insight into the molecular mechanism of MIF action, we have examined the role of MIF in the proliferation and intracellular signaling events of the well characterized, NIH/3T3 fibroblast cell line. Both endogenously secreted and exogenously added MIFs stimulate the proliferation of NIH/3T3 cells, and this response is associated with the activation of the p44/p42 extracellular signal-regulated (ERK) mitogen-activated protein kinases (MAP). The MIF-induced activation of these kinases was sustained for a period of at least 24 h and was dependent upon protein kinase A activity. We further show that MIF regulates cytosolic phospholipase A2 activity via a protein kinase A and ERK dependent pathway and that the glucocorticoid suppression of cytokine-induced cytoplasmic phospholipase A2 activity and arachidonic acid release can be reversed by the addition of recombinant MIF. These studies indicate that the sustained activation of p44/p42 MAP kinase and subsequent arachidonate release by cytoplasmic phospholipase A2 are important features of the immunoregulatory and intracellular signaling events initiated by MIF and provide the first insight into the mechanisms that underlie the pro-proliferative and inflammatory properties of this mediator.

3T3 Cells↗
PubMed1999

Minimally invasive aortic surgery: endovascular stent-graft repair of abdominal aortic aneurysm.

Minimally invasive surgical therapies are popular with patients and third party payors because they offer increased safety, decreased pain, as well as shorter recovery times and hospital stays when compared to standard open surgery. Minimally invasive aortic surgery is now a practical reality. Our experience with 150 endovascular stent-graft aortic aneurysm repairs at Baptist Hospital East is detailed in the following report. In our practice, stent-grafting is now the treatment of choice for infrarenal abdominal aortic aneurysms within the context of clinical trials.

Aged↗
PubMed1998

Screening for ophthalmic disease in older subjects using visual acuity and contrast sensitivity.

OBJECTIVE: Despite early interest in contrast sensitivity as a screening test for ophthalmic disease, most published opinion suggests that there is no benefit over conventional measurement of visual acuity. Taking a primary care perspective of screening, the authors evaluated the ability to discriminate those with any diagnosed ophthalmic disease in a large sample representative of the general population. DESIGN: Retrospective analysis of a clinical, cross-sectional survey. Snellen visual acuity, contrast sensitivity (Arden plates, American Optical contrast sensitivity test), and ophthalmic diagnosis were reported previously. PARTICIPANTS: A sample of 3283 subjects, all aged at least 50 years, were selected randomly from residents of a health district in Sydney, Australia. Ophthalmologic diagnosis (ophthalmic disease presence/absence) had been confirmed for 2522 of these subjects. MAIN OUTCOME MEASURES: Signal detection techniques (the receiver-operating characteristics function [ROC], quality ROC [QROC], and weighted kappa coefficient of association [kappa(r)]) were used to evaluate test discriminability. RESULTS: Because analyses of right and left eyes were almost identical, only right eye results are presented. Advantages of kappa(r) over ROC were shown. Discrimination of those with diagnosed ophthalmic disease from those without ophthalmic disease was best with Arden plate 7 (kappa0.5 = 0.93) and was better than distance Snellen visual acuity (kappa0.5 = 0.59). Arden plate 7 (6.4 cyc/deg) correctly assigned 96% of subjects at its optimal pass-fail criterion. CONCLUSIONS: In the primary care setting, a person older than 50 years of age with reduced contrast sensitivity, as determined by Arden plate 7, requires extra care in subsequent examinations because this person is likely to have an ophthalmic disease.

Aged↗
PubMed1997

Inhibition of S-nitrosation of reduced glutathione in aerobic solutions of nitric oxide by phosphate and other inorganic anions.

Reduced glutathione is nitrosated in aerobic solutions of nitric oxide under physiological conditions; however, the extent of S-nitrosation was found to be dependent on the inorganic anions present. Of nine anions tested, the bifunctional anions, arsenate, phosphate, and pyrophosphate (40 mM), inhibited the S-nitrosation reaction from 20 to 40%, whereas SO4(2-), H3BO3, SCN-, NO3-, Cl-, and acetate inhibited this reaction < or = 15%. A mechanism of inhibition is presented that involves the catalytic hydrolysis of N2O3 by the bifunctional anions; however, using [18O]phosphate as inhibitor, only 10% of the theoretically produced N2O3 was found to be hydrolyzed to nitrite via this mechanism as calculated from the loss of 18O from phosphate. We conclude that this mechanism accounts for only a minor part of the increased inhibition of S-nitrosation by these bifunctional anions.

Aerobiosis↗
PubMed1997

Predicting wheat yields: the search for valid and precise models.

Interest in predicting wheat yield in terms of physiological, cultural and meteorological variables is more than a century old. Early attempts involved statistical analyses of relationships between yield and observational data on precipitation, temperature, radiation, etc., and scientific study of physiological and cultural influences such as dates of sowing or anthesis, farming procedures and soil treatments. More recently these have been augmented by large-scale mechanistic models of phenological development, such as AFRCWHEAT, CERES and SIRIUS, incorporating some simulation facilities. All approaches implicitly involve fitting models of some sort: statistical, mechanistic or (preferably) a hybrid of these forms. Levels of success on this important matter are highly variable. After reviewing the field, we consider the results of recent efforts to contrast and evaluate the (large-scale) mechanistic approaches, using spatial/temporal methods for interpolating the required climatological input variables. The work employs a substantial database of wheat yields assembled for this purpose. After assessing the validity of the large-scale mechanistic models (with some intriguing conclusions), we then consider some results from a current approach to parsimonious hybrid modelling, based on statistical study of accessible climatological data interpreted in terms of physiological knowledge of key influences on plant development.

Models, Biological↗
PubMed1997

Evidence for DNA-PK-dependent and -independent DNA double-strand break repair pathways in mammalian cells as a function of the cell cycle.

Mice homozygous for the scid (severe combined immune deficiency) mutation are defective in the repair of DNA double-strand breaks (DSBs) and are consequently very X-ray sensitive and defective in the lymphoid V(D)J recombination process. Recently, a strong candidate for the scid gene has been identified as the catalytic subunit of the DNA-dependent protein kinase (DNA-PK) complex. Here, we show that the activity of the DNA-PK complex is regulated in a cell cycle-dependent manner, with peaks of activity found at the G1/early S phase and again at the G2 phase in wild-type cells. Interestingly, only the deficit of the G1/early S phase DNA-PK activity correlated with an increased hypersensitivity to X-irradiation and a DNA DSB repair deficit in synchronized scid pre-B cells. Finally, we demonstrate that the DNA-PK activity found at the G2 phase may be required for exit from a DNA damage-induced G2 checkpoint arrest. These observations suggest the presence of two pathways (DNA-PK-dependent and -independent) of illegitimate mammalian DNA DSB repair and two distinct roles (DNA DSB repair and G2 checkpoint traversal) for DNA-PK in the cellular response to ionizing radiation.

Animals↗
PubMed1997

Membership of the University of the Third Age (U3A) and perceived well-being.

To study the perceived well-being of members of the University of the Third Age (U3A) a sample of 975 members with a mean age of 67.9 +/- 6.98 years (range 50-94) was obtained from within the Greater Sydney Metropolitan Region and administered the Medical Outcomes Study (MOS) Short Form 36-item (SF-36) health survey. The SF-36 assesses eight health concepts; limitations in physical activities because of health problems; limitations in social activities because of physical or emotional problems; limitations in usual role activities because of physical health problems; bodily pain; general mental health; limitations in usual role activities because of emotional problems; vitality; and general health perception. Comparisons were made with USA normative peer groups, and the U3A sample scored as well as, or better than, their American peers. It is concluded that members of U3A had better-than-average general, physical and mental health, and that membership of U3A can, even in the very elderly, assist in conferring a much more positive perception of well-being.

Activities of Daily Living↗
PubMed1996

P/O ratios reassessed: mitochondrial P/O ratios consistently exceed 1.5 with succinate and 2.5 with NAD-linked substrates.

The efficiency of ATP synthesis coupled to cell respiration, commonly referred to as the P/O ratio, has been the subject of extensive studies for more that 50 years. The general conclusion from these studies is that respiring mitochondria can convert external ADP to ATP at a maximal P/O ratio of 3 for NAD-linked substrates and 2 for succinate. However, in recent years the validity of these "integral" values has been questioned on both mechanistic and thermodynamic grounds, and a mechanistic P/O ratio of 2.5 for NAD-linked substrates and 1.5 for succinate have been concluded on the basis of experiments with isolated mitochondria. These values have been widely adopted in the scientific literature, including several recent textbooks. In this paper we report that under optimal conditions with respect to preparation and assay procedures, the P/O ratios obtained with isolated rat liver mitochondria consistently exceed 2.5 with NAD-linked substrates and 1.5 with succinate. These results, although not excluding "nonintegral" P/O ratios due to various energy-dissipating side reactions, warrant caution in accepting the reported lower values and, in general, in referring to mechanistic considerations unless the underlying molecular mechanisms are understood.

Adenosine Diphosphate↗
PubMed1996

In vitro lymphocyte blastogenic responses and cytokine production in sickle cell disease patients with acute pneumonia.

BACKGROUND: Pulmonary infections continue to be a major cause of morbidity and mortality in patients with sickle cell disease (SCD). METHODS: In this study cell-mediated immunity in vitro was evaluated in 62 SCD patients (62 steady state and 16 with acute pneumonia) and compared with 44 normal controls (30 healthy and 14 with acute pneumonia). Lymphocyte blastogenic responses to phytohemagglutinin, tetanus toxoid and Candida albicans antigen were assessed in all subjects. In addition production of tumor necrosis factor, alpha- and gamma-interferon (IFN) were assayed. RESULTS: The results revealed comparable blastogenic responses to all three stimuli in all subjects except SCD patients with pneumonia. This group showed poor responses to all stimuli. The mean counts per minute were decreased 65 to 90% when compared with the other patients. Cytokine production of IFN-alpha and TNF was equivalent in all subjects. Conversely IFN-gamma production in both SCD groups, steady state (35 +/- 6 U/ml) and SCD with pneumonia (14 +/- 6 U/ml), was significantly decreased when compared with those in normal healthy controls (65 +/- 14 U/ml) and with pneumonia (48 +/- 17 U/ml). On analysis of individual titers 15 of 62 (24%) steady state and 10 of 16 (63%) SCD patients with pneumonia were deficient in IFN-gamma production in vitro. CONCLUSIONS: Acute pulmonary infections seem to have a profound effect on cell-mediated immunity in SCD. IFN-gamma deficiency, along with quantitative and qualitative T cell abnormalities, may represent significant factors to explain the frequent and severe infections seen in SCD.

Adolescent↗
PubMed1995

Hepatic metabolic response to injury and sepsis.

BACKGROUND: Experimental reports have indicated that hepatic oxidative and synthetic metabolism may become depressed in sepsis. Because the mechanism of infection-related liver dysfunction has not been established, further study of these functional alterations could contribute to the therapeutic management of septic organ failure syndromes. However, recently controversy has arisen over the existence of these derangements that must be reconciled before further progress in this field can be made. METHODS: Splanchnic balance studies for the measurement of glucose output and oxygen consumption were used to assess hepatic function in fasted normal volunteers (n = 18), injured patients (n = 10), and patients with sepsis (n = 18). The liver's contribution to splanchnic metabolism was estimated from a comparison of splanchnic oxygen utilization in response to increases in the liver-specific process of glucogenesis. In addition, in vivo liver albumin production was determined by using the [14C] carbonate technique. RESULTS: Glucose output after injury and sepsis was increased by 12.8% and 76.6%, respectively, compared with controls. On the basis of substrate balance studies, gluconeogenesis was estimated to account for 46%, 87%, and 93%, respectively, of splanchnic glucose output in each of the three groups. In patients with sepsis glucose output was also noted to be linearly related to regional oxygen consumption, indicating that these processes were coupled and increases in the respiratory activity of the splanchnic cellular mass could be accounted for by increases in new glucose output and gluconeogenic substrate clearance. The mean albumin synthetic rate increased during injury and sepsis by 22% and 29%, respectively, compared with normal volunteers. CONCLUSIONS: These studies cast doubt on the commonly held notion that tissue respiratory dysfunction may occur during sepsis. On the contrary, hepatic function is accelerated during hyperdynamic sepsis, and evidence indicating oxidative or synthetic functional depression is lacking.

Adult↗
PubMed1995

Serum interleukin-6 levels in the steady state of sickle cell disease.

In patients with childhood sickle cell disease (SCD) serum interleukin-6 (IL-6) levels were measured during the steady (healthy) state of disease. The corresponding measurements were made in comparable healthy normal controls. Serum IL-6 levels were assessed via ELISA in 27 SCD patients and 19 controls. Results revealed significantly higher circulating levels of IL-6 in the SCD patients (60 +/- 7 pg/ml) compared with the healthy controls (12 +/- 5 pg/ml). IL-6 is a multifunctional cytokine that plays a central role in host defense mechanisms. The impact of high circulating levels of IL-6 may be deleterious to humoral and cell-mediated immune functions in SCD, with resultant heightened risk for morbidity.

Adolescent↗
PubMed1994

Purification, bioactivity, and secondary structure analysis of mouse and human macrophage migration inhibitory factor (MIF).

The cytokine macrophage migration inhibitory factor (MIF) has been identified to be secreted by the pituitary gland and the monocyte/macrophage and to play an important role in endotoxic shock. Despite the recent molecular cloning of a human T-cell MIF, characterization of the biochemical and biological properties of this protein has remained incomplete because substantial quantities of purified, recombinant, or native MIF have not been available. We describe the cloning of mouse MIF from anterior pituitary cells (AtT-20) and the purification of native MIF from mouse liver by sequential ion exchange and reverse-phase chromatography. For comparison purposes, human MIF was cloned from the Jurkat T-cell line and also characterized. Mouse and human MIF were highly homologous (90% identity over 115 amino acids). Recombinant mouse and human MIF were expressed in Escherichia coli and purified in milligram quantities by a simple two-step procedure. The molecular weight of native mouse MIF (12.5 kDa monomer) was identical with that of recombinant mouse MIF as assessed by gel electrophoresis and mass spectroscopy. No significant post-translational modifications were detected despite the presence of two potential N-linked glycosylation sites. Recombinant MIF inhibited monocyte migration in a dose-dependent fashion, and both recombinant and native MIF-exhibited comparable biological activities. MIF induced the secretion of tumor necrosis factor-alpha and stimulated nitric oxide production by macrophages primed with interferon-gamma. Circular dichroism spectroscopy revealed that bioactive mouse and human MIF exhibit a highly ordered, three-dimensional structure with a significant percentage of beta-sheet and alpha-helix conformation. Guanidine hydrochloride-induced unfolding experiments demonstrated that MIF is of low to moderate thermodynamic stability. These studies establish the biochemical identity of native and recombinant MIF and provide a first insight into the three-dimensional structural properties of this critical inflammatory mediator.

Amino Acid Sequence↗
PubMed1994

The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor.

For over 25 years, the cytokine known as macrophage migration inhibitory factor (MIF) has been considered to be a product of activated T lymphocytes. We recently identified the murine homolog of human MIF as a protein secreted by the pituitary in response to endotoxin administration. In the course of these studies, we also detected MIF in acute sera obtained from endotoxin-treated, T cell-deficient (nude), and hypophysectomized mice, suggesting that still more cell types produce MIF. Here, we report that cells of the monocyte/macrophage lineage are an important source of MIF in vitro and in vivo. We observed high levels of both preformed MIF protein and MIF mRNA in resting, nonstimulated cells. In the murine macrophage cell line RAW 264.7, MIF secretion was induced by as little as 10 pg/ml of lipopolysaccharide (LPS), peaked at 1 ng/ml, and was undetectable at LPS concentrations > 1 microgram/ml. A similar stimulation profile was observed in LPS-treated peritoneal macrophages; however, higher LPS concentrations were necessary to induce peak MIF production unless cells had been preincubated with interferon gamma (IFN-gamma). In RAW 264.7 macrophages, MIF secretion also was induced by tumor necrosis factor alpha (TNF-alpha) and IFN-gamma, but not by interleukins 1 beta or 6. Of note, MIF-stimulated macrophages were observed to secrete bioactive TNF-alpha. Although previously overlooked, the macrophage is both an important source and an important target of MIF in vivo. The activation of both central (pituitary) and peripheral (macrophage) sources of MIF production by inflammatory stimuli provides further evidence for the critical role of this cytokine in the systemic response to tissue invasion.

Animals↗
PubMed1993

MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia.

Cytokines are critical in the often fatal cascade of events that cause septic shock. One regulatory system that is likely to be important in controlling inflammatory responses is the neuroendocrine axis. The pituitary, for example, is ideally situated to integrate central and peripheral stimuli, and initiates the increase in systemic glucocorticoids that accompanies host stress responses. To assess further the contribution of the pituitary to systemic inflammatory processes, we examined the secretory profile of cultured pituitary cells and whole pituitaries in vivo after stimulation with bacterial lipopolysaccharide (LPS). Here we identify macrophage migration inhibitory factor (MIF) as a major secreted protein release by anterior pituitary cells in response to LPS stimulation. Serum analysis of control, hypophysectomized and T-cell-deficient (nude) mice suggests that pituitary-derived MIF contributes to circulating MIF present in the post-acute phase of endotoxaemia. Recombinant murine MIF greatly enhances lethality when co-injected with LPS and anti-MIF antibody confers full protection against lethal endotoxaemia. We conclude that MIF plays a central role in the toxic response to endotoxaemia and possibly septic shock.

Acute-Phase Reaction↗
PubMed1993

Contrast sensitivity in elderly subjects with a diagnosed ocular disease.

In a random sample of 3283 subjects, 1266 right eyes and 1334 left eyes were diagnosed as having one of the following: age-related macular degeneration (ARMD), cataract, or glaucoma. In this same sample 1369 right eyes and 1312 left eyes had no ocular disease. All eyes had their contrast sensitivity measured using the Arden-type gratings manufactured by The American Optical Corporation. This is a large sample survey and although prevalence rates for the diseases examined may be inferred, this must be carried out with caution. I found for those eyes where the disease interfered with the integrity of the retina (ARMD, glaucoma) the mean contrast sensitivity scores were higher, in the middle and upper frequencies, than for those eyes with lens opacities. For frequencies above 0.4 cpd contrast sensitivities associated with diseased eyes were significantly (p < 0.001) reduced when compared to the same measures obtained on nondiseased eyes.

Aged↗