Histologic appearance of transmyocardial laser channels after 4 1/2 weeks

Preliminary results of clinical studies suggest that transmyocardial laser revascularization is an effective treatment for patients with chronic angina that cannot be treated by other means. The mechanism of this effect remains controversial. We present autopsy results from a patient obtained 4 1/2 weeks after operation that show that the channels do not maintain patency. Further work is needed to determine the frequency of channel patency and its relation to clinical benefit.     

FISH mapping and inter-Alu fingerprinting define the YAC contig map around the centromeric region of human chromosome 18

Previous reports concerning the location of D18S44 with respect to the centromere have been ambiguous. Also, it has not been possible, based on formerly reported markers, to show that contigs WC18.0 and WC18.1 overlap. However, the data presented here definitively show, using FISH technology, that D18S44 (located on WC18.0) maps to proximal 18q. Furthermore, inter-Alu fingerprinting shows a clear overlap between WC18.0 and WC18.1, thereby establishing a complete contig between D18S44 and markers from WC18.1.     

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women

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.     

RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1

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.     

Cerebral oxygenation during paediatric cardiac surgery: identification of vulnerable periods using near infrared spectroscopy

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.     

Expression of soluble VEGF receptor 2 and characterization of its binding by surface plasmon resonance

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.