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991.
RW Peck EJ Seaber RM Dixon GR Layton BC Weatherley SH Jackson PE Rolan J Posner 《Canadian Metallurgical Quarterly》1998,63(3):342-353
OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment. 相似文献
992.
PE Burnett RK Barrow NA Cohen SH Snyder DM Sabatini 《Canadian Metallurgical Quarterly》1998,95(4):1432-1437
The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase. The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood. Here, we show that RAFT1 directly phosphorylates p70(S6k), 4E-BP1, and 4E-BP2 and that serum stimulates RAFT1 kinase activity with kinetics similar to those of p70(S6k) and 4E-BP1 phosphorylation. RAFT1 phosphorylates p70(S6k) on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity. RAFT1 phosphorylation of 4E-BP1 on Thr-36 and Thr-45 blocks its association with the cap-binding protein, eIF-4E, in vitro, and phosphorylation of Thr-45 seems to be the major regulator of the 4E-BP1-eIF-4E interaction in vivo. RAFT1 phosphorylates p70(S6k) much more effectively than 4E-BP1, and the phosphorylation sites on the two proteins show little homology. This raises the possibility that, in vivo, an unidentified kinase analogous to p70(S6k) is activated by RAFT1 phosphorylation and acts at the rapamycin-sensitive phosphorylation sites of 4E-BP1. 相似文献
993.
PE Daubeney DC Smith SN Pilkington RK Lamb JL Monro VT Tsang SA Livesey SA Webber 《Canadian Metallurgical Quarterly》1998,13(4):370-377
OBJECTIVE: To determine the accuracy of three indirect blood pressure monitoring techniques (oscillometric technique [OS], Doppler [DOP], and optical plethysmography [OP] [blood pressure determined with a pulse oximeter waveform]) when compared with direct arterial pressure measurement in cats. STUDY DESIGN: Prospective study. ANIMAL POPULATION: Eight healthy (five female, three male), domestic short-hair cats weighing 3.5 +/- 0.8 kg METHODS: Cats were anesthetized with isoflurane. The inspired concentration of isoflurane was adjusted to produce mild hypotension (80 to 100 mm Hg direct systolic), moderate hypotension (60 to 80 mm Hg direct systolic), and severe hypotension (< 60 mm Hg direct systolic). Indirect pressure measurements were obtained from the thoracic limb and compared with concurrent direct measurement using regression analysis and a modification of Bland and Altman's technique. RESULTS: All three techniques underestimated systolic pressure. OS produced the best prediction of systolic pressure with a bias +/- precision of -15.9 +/- 8.1 mm Hg. DOP and OP were relatively inaccurate with a bias +/- precision of -25 +/- 7.4 mm Hg and -25 +/- 7.5 mm Hg. All three techniques correlated well with direct pressure with r values of 0.81, 0.88, and 0.88 for OS, DOP, and OP. DOP and OP provided an accurate prediction of direct mean arterial pressure with a bias +/- precision of -0.8 +/- 6 mm Hg and 0.6 +/- 5.5 mm Hg. Correlation was good between DOP and mean arterial pressure with r = 0.89. Correlation was also good between OP and mean arterial pressure with r = 0.90. CONCLUSIONS: OS provided the most accurate prediction of direct systolic pressure. DOP and OP provided a good prediction of mean arterial pressure in the cat. CLINICAL RELEVANCE: All three of these techniques are useful for detecting trends. Direct monitoring of blood pressure should be considered if accurate blood pressure measurement is required. 相似文献
994.
995.
996.
Vascular endothelial growth factor (VEGF) is an endothelial cell specific mitogen that induces angiogenesis in several pathological conditions. To block angiogenesis, soluble VEGF receptor can be used. In this study, we describe a method for high yield expression of soluble VEGF receptor 2 (sFlk-1) in a baculovirus expression system (30 mg purified sFlk-1 per L of insect cell supernatant). We also determined the binding constants for both human and mouse VEGF to the recombinant receptor by surface plasmon resonance. In this cell-free assay, under the given experimental conditions, the on-rate ka was 0.5-2.2 x 10(6) M-1s-1 and the off-rate kd was 2-4 x 10(-4) s-1 (KD = 2-6 x 10(-10) M). To our knowledge this is the first study to report on- and off-rates for the VEGF:sFlk-1 interaction. Heparin was not required for the binding of VEGF to sFlk-1 in this assay. The obtained values will serve as baseline parameters for the design of improved versions of recombinant soluble VEGF receptor. 相似文献
997.
In a group of 10 subjects, nine schizophrenic patients and one healthy twin (seven men and three women, i.e. two monozygotic twin pairs: two patients and a healthy man and his sick twin brother, one dizygotic pair of two female patients, three male patients and one female patient without their appropriate twin siblings) Halstead-Reitan Neuropsychological Battery (HRNB) was used and partial neuropsychological tests (Wechsler Memory Scale, the Stroop Color-Word Test, Tonal Memory). The parameters of white matter density were evaluated by computed tomography. The fundamental findings include: In our small group numerous statistically significant correlations were found between neuropsychological tests and white matter density. 2. Higher density is associated with poorer neuropsychological efficiency. There are very similar correlations between neuropsychological variables and density parameters in different areas of the brain. 4. The majority of correlations of neuropsychological parameters is from the area of tactile and motor functions. 5. It is striking that there are statistically significant correlations of density with the simultaneous performance of both hands and the performance of the non-dominant hand but not with the performance of the dominant hand alone. 6. Some correlations pertain in addition to density also to the very controversial problem of the brain size of schizophrenic patients. In the investigated group an association between better neuropsychological performance and larger size of the brain was found. All findings will have to be tested in larger groups of patients and healthy subjects. 相似文献
998.
The rotator cuff tear is an extremely common disorder in the general as well in the orthopaedic praxis. The etiology is multifactorial with intrinsic and extrinsic factors. Clinical assessment of the patient is important for an exact diagnosis and an individual treatment plan. The treatment options of full thickness tears include conservative as well as operative procedures. Over the last years, modified techniques have improved the results of rotator cuff reconstruction. 相似文献
999.
WJ Wells TW Prendergast F Berdjis D Brandl PE Lange R Hetzer VA Starnes 《Canadian Metallurgical Quarterly》1996,61(4):1168-1171
BACKGROUND: The benefit of coarctation repair in adults has been questioned by suggesting that hypertension may not be relieved by the operation and that surgical intervention may have no impact on the natural history of the disease. METHODS: To delineate the impact of surgical intervention on systolic hypertension, we conducted a retrospective review of 26 adults with a mean age of 32 +/- 10 years who underwent coarctation repair between 1987 and 1993. All patients were hypertensive (mean systolic blood pressure, 174 +/- 21 mm Hg; range, 140 to 220 mm Hg), and 18 patients (69%) were on a regimen of at least one hypertensive medication at the time of surgical admission. All patients underwent catheterization, and the mean peak systolic gradient across the coarctation was 61 +/- 25 mm Hg (range, 25 to 120 mm Hg). Operation included resection and end-to-end anastomosis (3 patients), resection with an interposition tube graft (6 patients), a bypass graft (11 patients), and patch angioplasty (6 patients). There was no hospital mortality or late morbidity. RESULTS: Intermediate follow-up was available at a mean of 2.3 +/- 2 years (range, 1 to 7 years). At last follow-up, the peak systolic gradient between the upper and lower body was trivial (< or = 10 mm Hg) in 23 patients (88%) and mild (11 to 20 mm Hg) in 3 (12%). All patients had significant improvement in systolic blood pressure (p < 0.001) compared to preoperative values, and the majority (23, 88%) were normotensive. More than half of the patients (14, 54%) were still on a regimen of antihypertensive medication at last follow-up, with a trend (p = 0.06) toward older patients requiring medication. CONCLUSIONS: Surgical repair of coarctation in adults is an effective, low-risk procedure, which results in a significant improvement in systolic hypertension and a decreased requirement of antihypertensive medications. 相似文献
1000.
AN Hodder PE Crewther ML Matthew GE Reid RL Moritz RJ Simpson RF Anders 《Canadian Metallurgical Quarterly》1996,271(46):29446-29452
Apical membrane antigen-1 (AMA-1) of Plasmodium falciparum is one of the leading asexual blood stage antigens being considered for inclusion in a malaria vaccine. The ability of this molecule to induce a protective immune response has been shown to be dependent upon a conformation stabilized by disulfide bonds. In this study we have utilized the reversed-phase high performance liquid chromatography of dithiothreitol-reduced and nonreduced tryptic digests of Plasmodium chabaudi AMA-1 secreted from baculovirus-infected insect cells, in conjunction with N-terminal sequencing and electrospray-ionization mass spectrometry, to identify and assign disulfide-linked peptides. All 16 cysteine residues that are conserved in all known sequences of AMA-1 are incorporated into intramolecular disulfide bonds. Six of the eight bonds have been assigned unequivocally, whereas the two unassigned disulfide bonds connect two Cys-Xaa-Cys sequences separated by 14 residues. The eight disulfide bonds fall into three nonoverlapping groups that define three possible subdomains within the AMA-1 ectodomain. Although the pattern of disulfide bonds within subdomain III has not been fully elucidated, one of only two possible linkage patterns closely resembles the cystine knot motif found in growth factors. Sites of amino acid substitutions in AMA-1 that are well separated in the primary sequence are clustered by the disulfide bonds in subdomains II and III. These findings are consistent with the conclusion that these amino acid substitutions are defining conformational disulfide bond-dependent epitopes that are recognized by protective immune responses. 相似文献