Heparin and neointimal thickening in an organ culture of human saphenous vein.
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Adenosine Triphosphate↗
Biomedical subjects
T Taylor
Publications and source records attributed to T Taylor.
A comparison of the high buoyant density proteoglycans isolated from the intervertebral discs of chondrodystrophoid and non-chondrodystrophoid dogs.
Groups of purebred beagles and greyhounds of similar ages (1.5-2.5 years) were used for the study. Intervertebral disc proteoglycans (PGs) were radiolabelled in vivo (with [35SO4(2-)], 24 hours and 60 days prior to euthanasia, when lumbar discs were dissected into nucleus pulposus (NP) and annulus fibrosus (AF). Aliquots of each disc region were separately analysed for total PG content as hexuronate. The remaining tissue was subjected to extraction with 4.0 M GuHCl. High buoyant density PGs were isolated from these extracts by CsCl density gradient ultracentrifugation. The hydrodynamic size and aggregatability of the 24-hour, 60-day-old, and resident PG populations were determined by Sepharose CL2B chromatography in the presence or absence of excess hyaluronic acid. While the hydrodynamic sizes of the newly synthesized (24-hour) disc PG preparations appeared to be similar, the 60-day-old greyhound disc PGs were found to be larger than the corresponding beagle disc PG populations. However, the keratan sulphate-core protein complexes prepared by chondroitinase ABC digestion of the newly synthesized (24 hour) disc PGs showed that the greyhound disc preparations were also larger than those from beagle discs. Approximately 80% of the newly synthesized PGs from beagle and greyhound discs were capable of aggregating with hyaluronic acid, however, this was reduced to 55% for the 60 day-old PGs in NP and AF and even less for the resident PG populations (as determined by hexuronate analysis). Significantly, PG aggregation was lower in the greyhound NP and AF preparations than in the corresponding PGs isolated from the beagle disc.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Intimal proliferation in an organ culture of human internal mammary artery.
OBJECTIVE: Intimal smooth muscle cell proliferation is an early feature of atherosclerosis. Its progression is difficult to monitor in humans and previous studies have mostly relied on necropsy material. The aim of this study was therefore to establish whether intimal proliferation occurred in an organ culture of human internal mammary artery. METHODS: Segments of freshly isolated internal mammary artery were maintained din standard tissue culture medium containing 30% calf serum for 14 d. Tissue viability (measured by ATP concentration) was maintained during processing and throughout the culture period [211(SEM 28) nmol ATP.g-1 wet weight on d 1 v 208(27) on d 14]. RESULTS: Histological transverse sections of cultured internal mammary artery showed the development of a neointima containing smooth muscle cells identified by immunocytochemistry for alpha actin. Pulse labelling of cultures with [3H]-thymidine showed proliferating cells predominantly in a neointimal layer with few dividing cells in the media. Cultured de-endothelialized vessels showed less neointimal thickening than cultured freshly isolated vessels [16(3) v 36(5) microns, p < 0.0025] as well as a reduced number of dividing cells per mm of neointimal length [3.1(0.6) v 5.5(1.1), p < 0.05]. CONCLUSIONS: Intimal proliferation occurred in organ culture of internal mammary artery. There is evidence for a factor derived from the endothelium, which may be important in the development of intimal proliferation.
Aged↗
Plasmodium falciparum: diversity of isolates from Malawi in their cytoadherence to melanoma cells and monocytes in vitro.
We observed considerable diversity in the cytoadherence of Plasmodium falciparum isolates from Malawi to melanoma cells, U937 cells and human peripheral monocytes. Each isolate exhibited a unique cytoadherence profile for the three human cell types. These isolates generally adhered well to U937 cells and fresh monocytes, moderately to melanoma cells and poorly to TE 671, MIA-Pa-Ca, WI 38, PLC/PRF/5 and HeLa cells. An antimalarial immunoglobulin pool inhibited binding to melanoma cells by 50% or more and to U937 cells by 25% or less. There was no correlation between in vitro cytoadherence to the three cells and clinical disease. These results suggest that malarial adherence ligands exposed on the surface of infected erythrocytes vary from one isolate to another.
Adolescent↗
Another cautionary note on the use of PCNA.
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Cell Division↗
Thyrotropin-releasing hormone regulation of human TSHB expression: role of a pituitary-specific transcription factor (Pit-1/GHF-1) and potential interaction with a thyroid hormone-inhibitory element.
Regulation of human thyrotropin beta subunit gene (TSHB) expression by thyrotropin-releasing hormone (TRH) was examined in a clonal rat pituitary-cell line (GH3). Transient expression studies were done with various 5'-flanking DNA sequences of TSHB coupled to reporter gene chloramphenicol acetyltransferase. Deletion analysis defined two discrete regions (-128 to -92 base pairs and -28 to +8 base pairs) that each mediated an approximately 2-fold TRH induction. The upstream site contains a DNA sequence with close homology to the DNA-binding site for a pituitary-specific transcriptional factor Pit-1/GHF-1. DNase I footprinting analysis of mouse thyrotropic tumor extract as well as DNA-transfection studies using an expression vector containing an N-terminal deletion of Pit-1/GHF-1 cDNA suggest that Pit-1/GHF-1 or a closely related protein in the thyrotroph mediates TRH responsiveness of this gene. In addition, the downstream site overlaps with the recently characterized thyroid hormone-inhibitory element of TSHB. In fact, deletion of DNA sequences important in thyroid hormone-receptor binding (c-erbAB/c-ERBA2) from +3 to +8 base pairs, significantly reduced (30%) TRH responsiveness. The location of a TRH-stimulatory element near a thyroid hormone-inhibitory element may allow for fine control of TSHB expression in vivo.
Animals↗
Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects.
The pharmacokinetics of the anti-inflammatory drug benzydamine were determined after intravenous infusion of 5 mg to six healthy male subjects. Benzydamine was characterized as a drug of relatively low systemic clearance (ca. 160 ml min-1) but high volume of distribution (ca. 1101); the apparent terminal half-life in plasma was ca. 8 h. Benzydamine was well absorbed after oral administration, as indicated by a mean systemic availability of 87 per cent. However, absorption of the drug was low (less than 10 per cent of the dose) after its use by male subjects as a mouthwash, or after its application to female subjects as dermal cream and vaginal douche preparations. The data suggest that benzydamine is generally not well absorbed through the skin and non-specialized mucosae, thereby limiting unrequired systemic exposure to this drug when it is used by these routes.
Administration, Cutaneous↗
Pharmacokinetics of pyridostigmine in dogs.
The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.
Administration, Oral↗
Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy subjects and in disease states.
The pharmacokinetics of ximoprofen, a potent new non-steroidal anti-inflammatory agent, has been investigated in normal healthy subjects and in patients with hepatic or renal disease. After intravenous infusion of 22.8 mg to healthy subjects, plasma ximoprofen concentrations declined in a polyexponential manner with a terminal phase half-life of 1.9 h. The systemic clearance of ximoprofen was 115 ml.min-1 and the volumes of distribution were 18.01 Vz and 13.81 Vss. Ximoprofen was 80-90% bound to plasma proteins. The systemic availabilities (f) of orally and rectally administered doses of 30 mg of ximoprofen were 98% and 56% respectively and, in the case of the rectal dose, absorption appeared to be prolonged leading to "flip-flop" kinetics. After single oral doses of 30 mg of ximoprofen to patients with hepatic disease, half-life (2.2 h), peak plasma concentrations (1.55 micrograms.ml-1 cf 1.04 micrograms.ml-1 in healthy subjects) and areas under the curve (6.12 micrograms.h.ml-1 cf 3.54 micrograms.h.ml-1 in healthy subjects) were significantly different from those in healthy subjects. After single oral doses of 30 mg of ximoprofen to patients with renal disease, pharmacokinetic parameters of half-life (4.0 h), mean residence time (6.0 h) and area under the curve (9.2 micrograms.h.ml-1) were significantly different from those in healthy subjects. There were no significant differences in pharmacokinetic parameters between patients having differing degrees of renal disease. These data nevertheless suggest that accumulation of ximoprofen in hepatic or renal disease would be of slight or negligible clinical relevance and that no alteration of the dose regimen (up to 15 mg twice daily) may be required when ximoprofen is administered in these disease states.
Adult↗
An open study to compare the pharmacokinetics, safety and tolerability of a multiple-dose regimen of azithromycin in young and elderly volunteers.
An open, parallel study was conducted to compare the pharmacokinetics of oral azithromycin in young and elderly healthy volunteers. A total of 12 young subjects (six males, six females) with a mean age of 29 (range 22-39) years and another 12 elderly subjects (six males, six females) with a mean age of 72 (range 67-80) years were given a standard five-day therapeutic regimen of azithromycin (500 mg single dose on day 1 and 250 mg once daily on days 2-5). Pharmacokinetic results indicated that Cmax, Cmin and urinary excretion were similar in the two age groups. Mean AUC0-24 was significantly greater (2.7 micrograms.h/ml) at day 5 in the elderly subjects compared with the younger age group (AUC0-24 = 2.1 micrograms.h/ml) (p = 0.041). Similarly, tmax values on days 1 and 5 were significantly greater in the elderly subjects; 3.8 h compared with 2.5 h in young subjects (p = 0.005) on day 1 and 4.4 h, compared with 3.2 h (p = 0.047) on day 5. There was also evidence of an inverse relationship between creatinine clearance and AUC0-24 (p less than 0.01) but not urinary excretion or Cmax. Despite these observations, it is concluded that the differences between the two age groups were of insufficient magnitude to warrant a dose modification in elderly subjects with only mild renal impairment. Side effects, chiefly headache and gastrointestinal symptoms, were reported by seven subjects in each group. No subject, however, was withdrawn from the study and there were no treatment-related abnormalities in any of the laboratory parameters measured.
Administration, Oral↗
Pharmacokinetics of the anti-inflammatory drug ximoprofen in healthy young and elderly subjects: comparison with elderly rheumatic patients.
The pharmacokinetics of ximoprofen were studied in young and elderly subjects after single and repeated doses up to 30 mg. In healthy elderly subjects (30 mg dose), a mean peak plasma drug concentration of 1.78 micrograms ml-1 +/- 0.83 s.d. occurred at a mean time of 1.95 h +/- 1.40 s.d. and, thereafter, concentrations declined monoexponentially with a mean half-life of 3.8 h +/- 1.4 s.d. Comparison of these data with those from younger healthy subjects showed that peak drug concentrations, areas under the curve and half-lives were about two-fold greater in the elderly, these differences probably reflecting a lower systemic drug clearance. Similar results were obtained on comparing data from young healthy subjects and elderly rheumatic patients receiving single and repeated doses of ximoprofen (15 mg twice daily). In patients, the half-life of ximoprofen was 2.5 h +/- 0.7 s.d. Within either group, pharmacokinetic parameters after single or repeated doses were similar: ximoprofen did not accumulate in the plasma of the young or elderly.
Adult↗
Pharmacokinetics of the anti-leishmanian agent WR 6026 in dogs.
The pharmacokinetics of the anti-leishmanial agent WR 6026 (8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride) has been studied after single intravenous infusion and oral doses of 5 mg (base)/kg to 6 Beagle dogs. After single intravenous infusions of 15 min, plasma concentrations of unchanged drug declined bi-exponentially from a mean maximum of 1203 ng/ml +/- 277 SD at the end of infusion to the limit of quantitation during 16 hours. After single oral doses, the mean Cmax of 23 ng/ml +/- 14 SD occurred at a mean Tmax of 2.2 hours +/- 1.3 SD. During 72 hours after the intravenous and oral doses, 0.6% and less than 0.2% of the dose respectively was excreted unchanged in the urine. The mean terminal-life of WR 6026 after the infusion doses was +/- 0.3 SD, but after the oral doses, plasma concentrations of drug were too low to allow estimation of the terminal half-life. The systemic clearance of WR 6026 (43.5 ml/min/kg) greatly exceeded the nomina, plasma flow (ca. 22 ml/min/kg) and indicated considerable extra-hepatic and extra-renal elimination of WR 6026 in dogs. The mean systemic availability of WR 6026 after the oral doses was ca.4%. The mean volumes of distribution of WR 6026 in dogs were 3.3 litres/kg +/- 1.1 SD (V(ss)) and 7.7 litres/kg +/- 2.4 SD (V(area)). These data characterise WR 6026 as a drug of relatively high systemic clearance, large volume of distribution, relatively short half-life and low systemic availability, probably due to presystematic elimination in the liver.
Administration, Oral↗
Determination of benzydamine and its N-oxide in biological fluids by high-performance liquid chromatography.
A simple, sensitive and selective method for the determination of benzydamine in human plasma and urine, and for benzydamine N-oxide in urine, has been developed using high-performance liquid chromatography in the reversed-phase mode. The limit of reliable determination of benzydamine in plasma was 0.5 ng/ml and that in urine 1 ng/ml; the limit of reliable determination of benzydamine N-oxide in urine was 50 ng/ml. The method has been successfully applied to the analysis of these compounds in biological fluids after administration of intravenous and oral doses of benzydamine to human volunteers.
Benzydamine↗
Thyroid hormone regulation of TRH mRNA levels in rat paraventricular nucleus of the hypothalamus changes during ontogeny.
The changing roles of the hypothalamus and pituitary in regulating thyroid hormone levels in the rat during ontogeny has not been fully elucidated. It has been reported that endogenous TRH begins to stimulate TSH secretion at 5-8 days after birth but that the pituitary responds to hypothyroidism during late gestation. To determine the onset and extent of TRH response to low thyroid hormone levels during ontogeny, normal and hypothyroid rats treated with methimazole for 7 days were sacrificed at 16 days gestation (E16), 20 days gestation (E20), 7, 21 and 56 days after birth (n = 5/study group). Plasma hormones were assayed from pregnant mothers, pups (pooled) and adults. Levels of TRH mRNA were measured in the paraventricular nuclei (PVN) by in situ hybridization histochemistry. A labeled 48-base cDNA oligonucleotide for TRH was hybridized with brain slices (n = 6/animal) in the region of the medial parvocellular division of the PVN of the hypothalamus and the signal was quantitated by digitized computer analysis. Plasma-free T4 levels decreased and plasma TSH levels increased in the animals treated with methimazole as compared to the euthyroid controls. TRH mRNA was detected in the PVN at E16 after brain slices were dipped in emulsion and granules observed by dark-field microscopy. In the euthyroid animals, TRH mRNA increased from E20 (150 +/- 9 OD units) to 7 days (222 +/- 5 OD units) and remained unchanged at 21 days (252 +/- 27 OD units) and 56 days (244 +/- 6 OD units).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The paraventricular nucleus of the hypothalamus has a major role in thyroid hormone feedback regulation of thyrotropin synthesis and secretion.
The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.
Animals↗
Pre-translational and post-translational regulation of TSH: relationship to bioactivity.
We are interested in the mechanisms by which endocrine and developmental factors regulate TSH synthesis at both pre-translational and post-translational levels. Thyroid hormone profoundly decreases transcription of the TSH beta gene, while TRH and agents modifying cyclic AMP increase transcription. To elucidate the molecular mechanisms underlying these effects, human embryonal kidney cells were transfected with constructs of the human TSH-beta gene fused to the chloramphenicol acetyl transferase gene. The first exon of human TSH-beta contains an element that increases basal expression and mediates T3-induced gene repression, probably through a direct interaction with c-erbA beta. In contrast, TRH and agents modifying cyclic AMP mediate increased transcription of TSH-beta through interacting with upstream regulatory elements. Thyroid hormone, TRH and developmental factors also regulate the branching pattern and relative sialylation of TSH carbohydrate chains, which may affect TSH action in vitro and in vivo.
Cell Line↗
Psychological impact of osseointegrated dental implants.
This longitudinal study of 39 patients who underwent treatment involving osseointegrated implants examined problems in oral and psychosocial functioning, expectations and experiences of difficulties with surgery, satisfaction with surgery, body image, neuroticism, self-concept, and extroversion. Patients completed six questionnaires from before phase 1 surgery to the final recall appointment for the new prosthesis (12 to 18 months after phase 1 surgery). The most common problems reported before treatment were those associated with eating; esthetics was less of a concern. Significant improvements in all problem areas were observed immediately after phase 2 surgery. Expectations of surgery-related problems were generally consistent with experiences immediately after phase 1 surgery, but more negative than experiences following phase 2 surgery. Body image before treatment was most negative vis-à-vis teeth. Significant improvements were found not only regarding teeth, but also on facial, mouth, and even overall body image. Satisfaction scores were generally high, but showed continued improvements through the final assessment. The only group experiencing negative outcomes consisted of patients scoring high on neuroticism.
Adult↗
Determination of the diuretic triamterene in the plasma and urine of humans by high-performance liquid chromatography.
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Chromatography, High Pressure Liquid↗