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Biomedical subjects

K Flanagan

Publications and source records attributed to K Flanagan.

15 recordsLinked to original sources
PubMed2005

Pneumococcal meningitis and etanercept--chance or association?

Rheumatoid arthritis is a severe deforming chronic disease which has major implications for mortality and quality of life. Agents with anti-tumour necrosis factor alpha (TNFalpha) activity are a new modality of therapy, which can significantly reduce the acute inflammation in this condition. However, TNFalpha is a cytokine involved in initiating the protective immune response; consequently, patients receiving this therapy are at increased risk of infection. Etanercept is a recombinant form of the p75 TNF receptor (TNF-RII) dimerised by fusion with a portion of the human IgG1 Fc tail with anti-TNFalpha activity. We report the first case of a patient with rheumatoid arthritis who developed pneumococcal meningitis whilst on etanercept, suggesting a possible association between etanercept and this severe life threatening infection.

Antirheumatic Agents↗
PubMed2001

Preoperative assessment: safety considerations for patients taking herbal products.

The increased use of herbal therapy and other dietary supplements in the past decade has increased the risk of complications for patients undergoing surgery. The use of herbal products is projected to rise in the United States. Therefore, it is important for the perianesthesia nurse to be aware of the herbal products that patients are taking and the possible anesthesia and/or surgical complications related to herbal products. Current resources are reviewed in this article to increase awareness for the perianesthesia nurse. Recommendations for establishing local protocols are given, and patient education on the use of herbal products is also considered.

Attitude to Health↗
PubMed2000

DNA-based vaccines for malaria: a heterologous prime-boost immunisation strategy.

A generic approach to inducing high level CD8+ T cell responses would be of value for prophylactic and therapeutic immunisation against several infectious diseases. However, it has been very difficult to achieve such immune responses using available vaccination strategies. Malaria is one of several diseases against which a new generation of better CD8+ T cell-inducing vaccines might be useful and is unusual in that it allows assessment of vaccine efficacy in small numbers of volunteers in carefully controlled challenge studies. Here we review the identification of a heterologous prime-boost regime using DNA priming and recombinant modified vaccinia Ankara (MVA) boosting that induces high level T cell responses in both mice and non-human primates. Clinical trials to determine whether this prime-boost approach is immunogenic in humans are in progress.

Adjuvants, Immunologic↗
PubMed1999

Low-doses of ionising radiation induce melanoma metastases and trigger the immune system--adrenal axis feedback loop.

Low-doses of ionising radiation are frequently implicated in triggering and/or accelerating the growth of skin and other malignancies. It seemed probable that the radiation at similar dose levels might initiate metastasis from already existing tumours. Highly pigmented human melanoma xenograft that had lost its ability for a spontaneous metastasising and grown subcutaneously in athymic mice was exposed to very low and well-defined doses of ionising radiation to determine whether low linear energy transfer radiation can restore metastatic potential of the tumour. To ensure that all effects derived from radiation-activated neoplastic cells only, I was delivered selectively to the cutaneous melanoma instead of using the external beam. The direct response of these tumours to radiation was monitored by determining the growth rate of the lesions. Histopathological methods were employed to detect metastases. The lowest radiation dose of approximately 6 cGy deposited in the tumours initiated metastatic spread in all animals. Gradual increase of the radiation doses diminished both the frequency of the appearance of metastases and their distance from the primary lesions. There were no metastases from non-irradiated melanomas. The highest dose used (60 cGy) did not affect significantly the growth of cutaneous (primary) tumours, but lower doses that enhanced inflammatory infiltration of the lesions reduced tumour growth. Such radiation-stimulated immune responses were accompanied by increased pigmentation in cutaneous lesions and activation of the adrenal cortex indicating that the immune system-adrenal axis feedback loop had been triggered. The results demonstrate that very low-doses of ionising radiation induce melanoma metastases. The phenomenon is accompanied by the stimulation of the immune system-adrenal axis feedback loop that regulates eicosanoid synthesis, thereby suggesting an involvement of these molecules in the process. Radiation doses approaching the therapeutic level do not initiate melanoma dissemination.

Adrenal Glands↗
PubMed1999

Furcation involvement in posterior teeth.

This article presents two cases in which different treatments were used for mandibular molars with furcation lesions. In the first case, a conventional amputation treatment of the distal root was performed to save the mesial root as a terminal tooth, which was used as a partial denture abutment. The second case describes a relatively new technique in which a root perforation was filled with graft material (synthetic bioglass) and covered with a resorbable membrane to treat an iatrogenic furcation lesion adjacent to the mesial root. Twelve months after surgery, periapical radiographs of both treated cases showed increased bone density. Follow-up in both cases--30 months in the first case and 12 months in the second--showed no pathological recurrence or clinical dysfunction. Root amputation may provide an alternative to extraction in periodontally involved molars. Synthetic bone replacement materials combined with guided tissue regeneration may also help to correct osseous defects incurred by recent furcation perforations with associated bone loss.

Aged↗
PubMed1998

Engineering an Mg2+ site to replace a structurally conserved arginine in the catalytic center of histidyl-tRNA synthetase by computer experiments.

Histidyl-tRNA synthetase (HisRS) differs from other class II aminoacyl-tRNA synthetases (aaRS) in that it harbors an arginine at a position where the others bind a catalytic Mg2+ ion. In computer experiments, four mutants of HisRS from Escherichia coli were engineered by removing the arginine and introducing a Mg2+ ion and residues from seryl-tRNA synthetase (SerRS) that are involved in Mg2+ binding. The mutants recreate an active site carboxylate pair conserved in other class II aaRSs, in two possible orders: Glu-Asp or Asp-Glu, replacing Glu-Thr in native HisRS. The mutants were simulated by molecular dynamics in complex with histidyl-adenylate. As controls, the native HisRS was simulated in complexes with histidine, histidyl-adenylate, and histidinol. The native structures sampled were in good agreement with experimental structures and biochemical data. The two mutants with the Glu-Asp sequence showed significant differences in active site structure and Mg2+ coordination from SerRS. The others were more similar to SerRS, and one of them was analyzed further through simulations in complex with histidine, and His+ATP. The latter complex sampled two Mg2+ positions, depending on the conformation of a loop anchoring the second carboxylate. The lowest energy conformation led to an active site geometry very similar to SerRS, with the principal Mg2+ bridging the alpha- and beta-phosphates, the first carboxylate (Asp) coordinating the ion through a water molecule, and the second (Glu) coordinating it directly. This mutant is expected to be catalytically active and suggests a basis for the previously unexplained conservation of the active site Asp-Glu pair in class II aaRSs other than HisRS.

Adenosine Triphosphate↗
PubMed1995

Solvent interactions with pi ring systems in proteins.

The interaction of water molecules with apolar amino acids is an important aspect of the hydrophobic effect and hence of protein folding. Our distributed multiple electrostatic model for water interacting with phenylalanine dipeptides shows that minimum energy sites exist above the aromatic ring such that a solvent molecule can interact with the pi electrons, but only when this site is not blocked by main-chain atoms or disturbed by main-chain polar atoms. This is consistent with the experimental evidence of others that water can hydrogen bond to aromatic pi electrons. In contrast, our analysis of solvent interactions with phenylalanine residues based on 48 high-resolution, well-refined protein structures shows that the dominant interaction of solvent molecules is with the edge of the ring and not with the pi elections. As the faces of phenylalanine rings tend to be buried, and solvent interactions with neighbouring polar atoms are more favourable, the interaction of water molecules with the faces of aromatic pi rings appears not to occur frequently in proteins.

Crystallography↗
PubMed1995

In vivo pharmacology of L-159,913, a new highly potent and selective nonpeptide angiotensin II receptor antagonist.

The present study was designed to characterize the in vivo pharmacology of L-159,913 (4-[[2'-(N-benzoylsulfamoyl)biphenyl-4-yl]-5butyl-2,4-dihydr o-2- [2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one); a potent All receptor antagonist. In normotensive rats, dogs, rhesus monkeys, and chimpanzees, L-159,913 inhibited All-induced elevations in blood pressure. In conscious rats, the relative potencies (ED50) were 0.51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o. doses exceeded 6 hr in rats. L-159,913 was 3 times less potent than losartan in rats and equipotent to losartan in monkeys. All induced elevation of plasma aldosterone in rats was also inhibited by L-159,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute dose of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 mg/kg, iv) in this renin dependent animal model. In conscious normotensive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliuretic response with no effect on glomerular filtration rate, effective renal plasma flow or filtration fraction, suggesting a tubular site of action. L-159,913 is a selective and potent All receptor antagonist with good oral activity, long duration of action and antihypertensive efficacy.

Aldosterone↗
PubMed1989

Early exercise testing and discharge of patients with acute chest pain syndromes.

Forty-nine patients deemed to have a low in-hospital risk after 24 hours observation for suspected myocardial infarction, underwent exercise testing 24-48 hours after admission. Thirty-six patients had adequate exercise tolerance and follow-up of this group at one year, showed that no major cardiac event occurred. Of the 13 patients whose performance was inadequate, five were found to have critical lesions at angiography. Early exercise testing is a useful prognostic test, permitting confident early discharge of patients who do not have threatening coronary disease. If this approach was adopted throughout the country, the number of patients, referred for angiographic assessment prior to loss of myocardium could be substantially, and justifiable increased.

Electrocardiography↗
PubMed1987

Group A beta-hemolytic streptococcal skin infections in a US meat-packing plant.

In 1985, the second reported outbreak of group A beta-hemolytic streptococcal (GABHS) skin infections among US meat packers was recognized at an Oregon meat-packing plant. All 69 plant workers were interviewed and examined for the presence of pustular, draining, or inflamed lesions. During a three-month period, 44 episodes of skin infection occurred in 32 workers, all but four of whom worked in boning or killing areas. Acquiring infection was associated with job category (relative risk [RR], 5.7; 95% confidence intervals [CI], 2.9 to 11.3) and having at least two hand lacerations (RR adjusted for occupation, 6.2; 95% CI, 3.0 to 12.5). Group A beta-hemolytic Streptococcus (18), Staphylococcus aureus (12), or both (20) were isolated from 70 lesions cultured. Meat is suspected as a vehicle of transmission because cultures of two meat specimens contained the same GABHS strain as did 24 isolates from patients. Increasing reports of GABHS skin infections in meat packers suggest that this occupational risk may be more common than is realized.

Abattoirs↗
PubMed1982

Involvement of dolichol phosphates as intermediates in the mannosyl and galactosyl transferases of rat testicular germ cell Golgi apparatus membranes.

Isolated Golgi apparatus membranes from the germinal elements (spermatocytes and early spermatids) of rat testis were examined for their ability to incorporate [14C]mannose and [14C]galactose into glycolipid and glycoprotein fractions. Transfer of mannose from GDP-[14C]mannose into a Lipid I fractions (GPD:MPP mannosyl transferase activity), identified as mannosyl phosphoryl dolichol, showed optimal activity at 1.5 mM manganese and at pH 7.5. Low concentrations of Triton X-100 (0.1%) stimulated transferase activity in the presence of exogenous dolichol phosphate (Dol-P); however, inhibition occurred at Triton X-100 concentrations greater than 0.1%. Maximal activity of this GDP:MPP mannosyl transferase occurred at 25 microM Dol-P. Activity using endogenous acceptor was 2.34 pmole/min/mg, whereas in the presence of 25 microM Dol-P the specific activity was 284 pmole/min/mg, a stimulation of 125-fold. Incorporation of mannose into a Lipid II (oligosaccharide pyrophosphoryl dolichol) and a glycoprotein fraction was also examined. In the absence of exogenous Dol-P, rapid incorporation into Lipid I occurred with a subsequent rise in Lipid II and glycoprotein fractions suggesting precursor-product relationships. Addition of exogenous Dol-P to galactosyl transferase assays showed only a minor stimulation, less than twofold, in all fractions. Over the concentration range of 9.4 to 62.5 micrograms/ml Dol-P, only 1% of radioactive product accumulated in the combined lipid fractions. These observations suggest that the mannose transfer involves Dol-P intermediates and also that spermatocyte Golgi membranes may be involved in formation of the oligosaccharide core as well as in terminal glycosylations.

Animals↗
PubMedDate not supplied

A cross-sectional study of ethylene glycol monomethyl ether process employees.

Human exposures to ethylene glycol monomethyl ether have been associated with hematological and neurological abnormalities. Recent animal toxicology studies have also reported testicular atrophy. To determine whether employees potentially exposed to ethylene glycol monomethyl ether during manufacturing and packaging had a higher prevalence of anemia, leukopenia, or sterility than an in-plant comparison group, a cross-sectional study was conducted at the Michigan Division of Dow Chemical U.S.A. Blood samples on 65 of 97 potentially exposed and control white males, and semen samples from a subset of 15 were analyzed. With the possible exception of smaller testicular size, no gross abnormalities or clinically meaningful differences in hematological or fertility indices were noted. Results of regression modeling suggested that white blood cells and hemoglobin might be decreased at higher exposure levels.

Adult↗