Prone or supine for preterm babies?
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Humans↗
Biomedical subjects
M Lee
Publications and source records attributed to M Lee.
Sequence specific molecular recognition by a monocationic lexitropsin of the decadeoxyribonucleotide d-[CATGGCCATG]2: structural and dynamic aspects deduced from high field 1H-NMR studies.
All 1H-NMR resonances of d-[CATGGCCATG]2 and the 1:1 complex of lexitropsin 1 and the DNA were assigned by the NOE difference, COSY and NOESY methods. Addition of 1 causes the base and imino protons for the sequence 5'-CCAT to undergo the most marked drug-induced chemical shift changes, thereby indicating that 1 is located in this base pair sequence. NOEs confirmed the location and orientation of the drug in the 1:1 complex, with the amino terminus oriented to C(6). The van der Waals interaction between H12a,b of 1 and AH2(8) may be responsible for reading of the 3' A.T base pair in the 5'-CCAT sequence. Exchange NMR effects allow an estimate of approximately equal to 62 s-1 for the intramolecular "slide-swing" exchange of the lexitropsin between two equivalent binding sites with delta G = 58 +/- 5 kJ mol-1 at 301 degrees K.
Computer Simulation↗
Structural and dynamic aspects of binding of a prototype lexitropsin to the decadeoxyribonucleotide d(CGCAATTGCG)2 deduced from high-resolution 1H NMR Studies.
Structural and dynamic properties of the self-complementary decadeoxyribonucleotide d(CGCAATTGCG)2 and the interaction between a prototype lexitropsin, or information-reading oligopeptide, and the decadeoxyribonucleotide are deduced by using high-resolution 1H NMR techniques. The nonexchangeable and imino proton resonances of d(CGCAATTGCG)2 have been completely assigned by two-dimensional NMR studies. The decadeoxyribonucleotide exists as a right-handed B-DNA. In the 1H NMR spectrum of the 1:1 complex, the selective chemical shifts and removal of degeneracy of AH2(4), AH2(5), T-CH3(6), and T-CH3(7) due to the anisotropy effects of the heterocyclic moieties of the ligand, and with lesser effects at the flanking base sites C(3) and G(8), locate the drug centrally in the decadeoxyribonucleotide. This conclusion is supported by plots of individual chemical shift changes across the decadeoxyribonucleotide. Similarly, imino protons IV and V experience larger shifts and II and III smaller shifts in accord with this conclusion while drug complexation permits the detection of imino proton I. Strong nuclear Overhauser effects (NOEs) between pyrrole H5 and AH2(5), and weaker NOEs to AH1'(5), TH3'(6), and AH2'(5), firmly locate the ligand in the minor groove. Intraligand NOEs between the adjacent heterocyclic moieties indicate that the lexitropsin is subject to propeller twisting about the N6-C9 bond in both the bound and free forms. Nuclear Overhauser effect spectroscopy (NOESY) and correlated spectroscopy (COSY) experiments also indicate that the removal of degeneracy of the C16 methylene protons upon complexation may arise from restricted rotation about the C15-N9, C15-C16, and C16-C17 bonds. Specific hydrogen bonds between amide NH groups on the concave face of the ligand (N4H, N6H, N9H) and adenine N3 or thymine O2 on the floor of the minor groove are in accord with displacement of the hydration shell by the drug. NOE measurements on the decadeoxyribonucleotide in the 1:1 complex confirm it exists as a right-handed helix and belongs to the B family. Exchange NMR effects permit an estimate of a rate of approximately equal to 44 s-1 for the two-site exchange of the lexitropsin between two equivalent sites on the decamer with delta G++ approximately equal to 70 +/- 5 kJ mol-1 at 294 K. Alternative mechanisms for this exchange process are considered.
Base Sequence↗
Clinical predictors of severe head trauma in children.
We reviewed the medical records of 55 patients who underwent a cranial computed tomographic (CT) scan for acute head trauma. The severity of head trauma was classified according to objective clinical findings as severe in 44 patients, moderate in three, and mild in eight. Thirty-seven patients (84%) with severe head trauma had a brain injury identified on CT scan. Six patients with severe head trauma had a Glasgow Coma Scale score of 12 or greater and an abnormal CT scan. All patients with mild or moderate head trauma had normal CT scans. Severe head trauma, as defined in this study, accurately identified all patients with abnormal CT scan findings. We conclude that a classification based on objective clinical findings accurately identifies the severity of head trauma. This is particularly important in evaluating patients with a Glasgow Coma Scale score of 12 or greater. A prospective study including larger numbers of patients is needed to further evaluate such a classification.
Adolescent↗
Thermal dose-response of magnetic-induction thermoradiotherapy.
Sixty-three patients with advanced cancer underwent greater than or equal to 5,000 cGy combined with Concentric Coil magnetic-induction localized hyperthermia. Tumor regression (CR + PR) was compared to thermal dose received, incorporating the premise that hyperthermia response is a function of time as well as temperature. A computer program was developed (after Sapareto and Dewey [2]) which stored minimum tumor temperatures recorded spatially and temporally during treatment and correlated response with T43 (equivalent minutes at 43 degrees C during the first treatment) and CT43 (cumulative T43, computed by multiplying T43 by the actual number of identical subsequent treatments received during the course of therapy). Those who responded--N = 46 (73%)--had significantly higher median thermal doses than those who did not respond. Comparison of T43 and CT43 thermal dose values between responders and nonresponders was significantly different at p values of 0.05 and 0.04, respectively. The data indicate that magnetic-induction hyperthermia and high-dose XRT was an effective treatment combination in advanced disease and that tumor response improved as thermal dose increased.
Combined Modality Therapy↗
Abnormalities of the hematopoietic regulatory network.
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Adult↗
Secretion of lipoprotein lipase from myocardial cells isolated from adult rat hearts.
Heparin (5 U/ml) induced the release of LPL into the incubation medium of cardiac myocytes isolated from adult rat hearts. The secretion of LPL occurred in two phases: a rapid release (5-10 min of incubation with heparin) that was independent of protein synthesis followed by a slower rate of release that was inhibited by cycloheximide. The rapid release of LPL induced by heparin likely occurs from sites that are at or near the cell surface. LPL secretion could also be stimulated by heparan sulfate and dermatan sulfate, but not by hyaluronic acid, chondroitin sulfate or keratan sulfate. Heparin-releasable LPL activity measured in short-term incubations represented a large fraction (40-50%) of the initial LPL activity associated with myocytes, but the fall in cellular LPL activity following heparin was less than the amount of LPL activity secreted into the incubation medium. This discrepancy was not due to latency of LPL in the pre-heparin cell homogenates, but in part could be due to a three-fold greater affinity of the heparin-released enzyme for substrate as compared to LPL in post-heparin myocyte homogenates.
Animals↗
The effects of intravenous L-dopa on plasma renin activity, renal function, and blood pressure in man.
L-dopa 7 micrograms.kg-1.min-1 was given intravenously over 2 h to six healthy subjects, controlled by an infusion of saline on a separate occasion, with measurement of plasma renin activity (PRA), urinary sodium and potassium excretion, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), blood pressure, and pulse rate. Mean PRA fell by 50% following L-dopa, which was significantly different from the slight rise which occurred after saline infusion. There was a significant increase in urinary sodium excretion and effective renal plasma flow on infusion of L-dopa. Mean diastolic blood pressure fell during L-dopa infusion, in contrast to the slight increase which occurred during the control study. These observations confirm the anticipated renal dopaminergic effects of L-dopa and also suggest a dopaminergic influence on renin release in man.
Adult↗
Interrelations of empathy, cognition, and moral reasoning with dimensions of juvenile delinquency.
The interrelations of a variety of indices of sociocognitive development (empathy, role-taking, logical cognition, and moral reasoning) were studied in delinquent and nondelinquent adolescents. Delinquent males (grouped into psychopathic, neurotic, and subcultural subgroups) and a matched nondelinquent comparison group were administered individually two empathy scales (the Davis Interpersonal Reactivity Index and the Mehrabian and Epstein Questionnaire Measure of Emotional Empathy), an adaptation of Byrne's and Flavell's role-taking tasks, two Piagetian cognitive tasks, and two of Kohlberg's structured moral dilemmas. Delinquents as a group displayed significantly more immature modes of role-taking, logical cognition, and moral reasoning than did nondelinquents. The delinquent subgroups, however, did not significantly differ from one another on these dimensions. Role-taking, logical cognition, and moral reasoning were significantly related to one another. Anticipated differences in level of empathy between the delinquent and nondelinquent adolescents failed to occur. A number of interpretations for this unexpected finding are offered.
Adolescent↗
Percutaneous transluminal angioplasty in the treatment of lower limb ischaemia.
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Adult↗
Inferior vena cava thrombosis. Unusual presentation of testicular tumor.
We report an unusual case of testicular tumor presenting as thrombosis of the inferior vena cava. However, in contrast to a previous report, thrombosis in this patient was not caused by compression of the vena cava by neoplasm metastases. In our patient, we postulate that tumor invaded the vena cava and that thrombosis was exacerbated by a hypercoagulable state induced by the tumor.
Adult↗
Humoral hypercalcemia due to squamous cell carcinoma of renal pelvis.
We describe an unusual and rare case of humoral hypercalcemia due to Stage D squamous cell carcinoma of the renal pelvis in a patient with no evidence of bony metastases. The literature on humorally mediated hypercalcemia associated with epithelial tumors of the renal pelvis is reviewed.
Adult↗
Mortality patterns among hypertensives by reported level of caffeine consumption.
The effect of caffeine consumption on mortality was evaluated in a historical cohort study of 10,064 diagnosed hypertensive individuals participating in the Hypertension Detection and Follow-up Program from 1973 to 1979. Total caffeine intake level from beverages (coffee and tea) and certain medications, was estimated at the 1-year visit. No evidence was found supporting an association between increased level of caffeine consumption and increased all-cause mortality or cardiovascular disease mortality during the following 4 years. Cigarette smoking was significantly associated with mortality; the association being more pronounced among non- and low-caffeine consumers for all-cause mortality and among non-caffeine consumers for all cardiovascular mortality except cerebrovascular mortality.
Adult↗
Cell cycle control genes in fission yeast and mammalian cells.
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CDC2 Protein Kinase↗
Pentobarbital augments serotonin-mediated inhibition of cerebellar Purkinje cells.
The ability of pentobarbital to modify the direct effects of iontophoretically ejected serotonin on the firing rates of cerebellar Purkinje cells was examined. Serotonin elicited inhibition, excitation, or a biphasic effect on cerebellar Purkinje cells. With continuous application of iontophoretic pentobarbital at currents found to potentiate GABA-induced inhibition, serotonin-mediated inhibitions were also augmented consistently. When application of serotonin elicited excitation, including a late component of biphasic responses, iontophoretic pentobarbital converted the effect to, primarily, inhibition. Besides increasing the magnitude of serotonin-mediated inhibition, iontophoretic pentobarbital increased the duration of this effect. In another series of experiments using pentobarbital rather than urethan as the anesthetic, serotonin-mediated inhibition was significantly augmented for all ejection currents tested. The GABA antagonists bicuculline, pentylenetetrazole and picrotoxin attenuated pentobarbital augmentation of serotonin-elicited inhibition. We conclude that serotonin-mediated inhibition of Purkinje cells is modifiable by pentobarbital and this effect bears a strong semblance to the actions of barbiturates on GABAergic neurotransmission.
Action Potentials↗
Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.
Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by chance. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.
Adult↗
Structural and dynamic aspects of the sequence specific binding of netropsin and its bis-imidazole analogue on the decadeoxyribonucleotide d-[CGCAATTGCG]2.
High field 1H-NMR techniques have been used to examine the sequence dependent binding of a lexitropsin, the bis-imidazole analogue of netropsin 1, to the decadeoxyribonucleotide d-[CGCAATTGCG]2. The non-exchangeable and imino protons of the 1:1 lexitropsin:DNA complex are assigned by 1D-NOE difference and COSY methods. Addition of 1 to the DNA resulted in marked drug induced chemical shift changes of both the non-exchangeable and imino protons of A(4,5) and T(6,7). These results suggest that the lexitropsin is located in the minor groove along A(4) to T(7) of the DNA. Weaker chemical shift changes are observed for C(3) and G(8) which suggest that the bisimidazole moiety of 1 can also accept G.C sites. Specific NOEs seen between the lexitropsin (H2, H14 and H15) and DNA (AH2(4) and AH2(5] confirmed that the N to C-terminii of 1 is, on average, bound centrally to the sequence in the direction 5'-AATT-3'. However, netropsin 2 is shown to bind tightly only to the AATT sequence. Exchange NMR effects permit the estimate of the rate of exchange of the lexitropsin 1 between the two equivalent sites on the DNA to be approximately 160s and 24s for netropsin under comparable conditions. Several factors contributing to the sequence specificity of lexitropsin binding are discussed.
Base Sequence↗
Sequence specific molecular recognition and binding of a monocationic bis-imidazole lexitropsin to the decadeoxyribonucleotide d-[(GATCCGTATG).(CATACGGATC)]: structural and dynamic aspects of intermolecular exchange studied by 1H-NMR.
The non-exchangeable and imino proton NMR resonances of the non self-complementary decadeoxyribonucleotide d-[(GATCCGTATG).(GATACGGATC)] as well as those of the 1:1 complex of the monocatonic bis-imidazole lexitropsin 1 to this sequence have been assigned by using a combination of NOE difference, COSY and NOESY techniques. Confirmation of complete annealing of the two non self-complementary decamer strands to give the duplex decadeoxyribonucleotide is obtained by the detection of ten imino protons. It is established that the sugar-base orientations of all the bases in the duplex decamer are anti. From NOE studies, it is concluded that the duplex oligomer is right-handed and adopts a conformation in solution that belongs to the B family. A population analysis reveals that the sugar moieties exist predominantly in the S-form (2'-endo-3'-exo). Addition of 1 to the DNA solution leads to doubling of the resonances for CH6(4,5), GH8(6), TH6(7) and T-CH3(7). The base, anomeric H1' and imino proton signals for the base sequence 5'-CCGT undergo the most marked drug-induced chemical shift changes. These results provide evidence that the lexitropsin is bound to the sequence 5'-CCGT in the minor groove of the DNA. NOE measurements between the amide protons (NH1 and NH4) and the imino proton (IV and V) signals confirmed the location and orientation of 1 in the 1:1 complex, with the imino terminus oriented to C(4). The specific binding of 1 to the sequence 5'-CCGT-3' deduced in this study is in agreement with the footprinting data obtained using the Hind III/Nci fragment from pBR322 DNA [Kissinger et al. 1987 (13)]. Intramolecular NOEs observed between H4 and H9 of the lexitropsin suggest that the molecule is not planar, but subjected to propeller twisting, in both the free and bound forms. Furthermore, NOE measurements permit assignment of the DNA duplex in the 1:1 complex to the B-form, which is similar to that of the free DNA. The [(T7A8T9).(A12T13A14)] segment of the DNA shows better stacking, by propeller twisting, compared to the rest of the molecule in the free as well as the complex forms. The intermolecular rate of exchange of 1 between the equivalent 5'-CCGT sites, at a concentration of 12 mM, is estimated to be approximately 88s-1 at 308 degrees K with delta G not equal to of 63 +/- 5 KJ mol-1.
Base Sequence↗