Determination of the antitumor agent depsipeptide in plasma by liquid chromatography on serial octadecyl stationary phases

We have cloned the rat fibroblast growth factor-2 (FGF-2) promoter region including 1058 base pairs (bp) of 5'-flanking DNA. Complete sequencing of this promoter region revealed a 74 bp domain between nucleotides-793 and-720 that was greater than 97% A/G-rich. A repeat of the sequence 5'-AGGGAGGG-3' separated by 11 bp was located at the core of this domain. A 37 bp A/G-rich oligonucleotide containing these AGGG-repeat sequences was synthesised, and tested for function on a minimal herpes simplex virus thymidine kinase (TK) promoter, fused to the firefly luciferase gene (TKp.luc), in transiently transfected neonatal rat cardiac myocytes. Promoter activity was stimulated approximately 3 fold in the presence of AGGG-repeat sequences. This effect was neither tissue or species-specific since TK promoter activity was increased approximately 11 fold in both rat and human glial tumor cells. Four specific complexes (Cl-4) were detected between neonatal rat heart nuclear proteins and the 37 bp A/G-rich oligonucleotide by gel mobility shift assay. Competition with excess unlabelled 37 bp A/G-rich oligonucleotide revealed that two complexes represented very high affinity/specificity interactions (C2 > C4) while Cl and C3 were of lower affinity. As a result, competition with up to a 25 fold molar excess of 37 bp A/G-rich oligonucleotide led to the loss of C2 and C4, and a corresponding and transient increase in the levels of Cl and C3, which themselves were reduced with more competitor oligonucleotide. The AGGG-repeat resembles the 5'-gGGGAGGG-3' sequence previously implicated in the response of the atrial natriuretic factor promoter to the alpha-adrenergic agonist, phenylephrine. Although an additional 1.5 fold increase in TK promoter activity was detected in the presence of the 37 bp A/G-rich oligonucleotide with phenylephrine treatment of transfected myocytes, this effect was not statistically significant. Furthermore, there was no difference in the gel mobility shift (Cl-4) pattern obtained with the 37 bp A/G-rich oligonucleotide and nuclear protein isolated from neonatal rat cardiac myocytes grown in the presence or absence of norepinephrine. These data suggest that the A/G rich sequences in the rat FGF-2 gene 5'-flanking DNA, including the AGGG-repeat, are able to confer stimulatory activity on a promoter in a tissue- and species-independent manner, but alone are not able to induce a significant phenylephrine response in neonatal rat cardiac myocytes.     

Seasonal Phosphate Demand for Lake Erie Plankton

From April to mid-October 1979, in the eastern and central basins of Lake Erie, the pattern for phosphate demand was assessed by four independent methods: conventional monitoring, measurements of polyphosphate, phosphate turnover time, and a newly developed phosphate deficiency index. Thermal stratification and P limitation occurred faster in the central than in the eastern basin and the plankton remained P limited throughout most of the stratified season. This condition relaxed as the thermocline deepened in the central basin, exposing the epilimnion to a greater area of sediments. In September, when mixing of the entire water column occurred, the plankton were no longer P limited. In contrast, as the thermocline deepened in the eastern basin, metalimnetic water was entrained but the plankton remained P limited until mid-October. These observations support the view that a reduction of phosphorus in Lake Erie would probably affect the phytoplankton biomass during the periods of P limitation.     

Montgomery Lecture, 1975. Changing concepts of the prognosis and management of small malignant melanomas of the choroid

Recent studies have shown conclusively that patients with small choroidal melanomas tend to have a favourable prognosis and that this, in turn, is closely related to tumour cell type, mitotic activity, degree of trans-scleral extension, and other characteristics of the tumour. It has not yet been established whether enucleation of the tumour-containing eye increases or decreases the patient's chance for survival. The frequency with which we observe late metastatic deaths among patients who had seemingly been 'cured' by enucleation indicate that host factors are most important in determining whether or not a patient will succumb to his tumour. It is possible that nonsurgical methods of treatment may be as effective or even more effective than enucleation (a) by diminishing the changes of intravasation of tumour cells, and (b) by promoting a more favourable host response to the tumour. While the total experience in management by methods other than enucleation is small, the results reported to date with photocoagulation, radiation, and no therapy are encouraging. Only after a much larger experience with prolonged periods of evaluation (more than 10 years after recognition of the tumour) will we be able to compare the results with those obtained by enucleation.     

Comparative vasodilator effects of nitroglycerin, pentaerythritol trinitrate and biometabolites, and other organic nitrates

Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasodepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose-response curves established for nitroglycerin (ng), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20 percent, erythrityl tetranitrate 12 percent, and isosorbide dinitrate 3.5 percent. The ratios of vasodilator activity of PE trinitrate and its metabolities were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE O. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.     

Therapeutic equivalency of two lidocaine preparations

Twenty-five volunteers were studied as to the onset and duration of action of two commercial brands of lidocaine. One and two percent concentrations of the preparations were tested intradermally using a double-blind, cross-over protocol. Both needle-drop and electrical stimulation techniques were employed as the source of pain stimulus. Five additional subjects were studied in a dose-ranging study using a placebo and lidocaine concentrations of 0.25%, 0.50%, 0.75% and 1.0%; this experiment was conduced to determine the sensitivity of the experimental methods. Both the needle-drop and electrical stimulation techniques were able to distinguish the 0.25% preparation from placebo and from the other concentrations of 1% and 2%. The two preparations were found to be statistically equivalent at concentrations of 1% and 2% and could be used interchangeably in clinical procedures.     

Safety restraints for children travelling in motor vehicles

The parents of 202 children were questioned about their use of safety restraints for their children while they were passengers in a motor vehicle. The result of the survey shows a low incidence of use of safety restraints by both parents and their children and that the type used for children was, in the majority of cases, both inadequate and dangerous. There was a correlation between the use of safety restraints by both parent and child on the day of questioning, but no association was found between the use of these restraints and the social class, educational standard achieved, income group, home language or home province of the parents. Neither was there any association between the use of safety restraints and a history of previous traffic accidents which had involved the family or close friends. In South Africa, the number of deaths in childhood as a result of motor vehicle accidents exceed those from the same cause in the United Kingdom. We consider that the medical profession in this country should inform the public of the desirability of fitting and using safety restraints of the correct type for children while they are passengers in motor vehicles. Reasons for the high incidence of serious injuries to children who are passengers in motor vehicles are reviewed and the methods of restraining children of different ages are discussed.     

A note on the contributions of Cotterill, Castigliano, Crotti and Engesser to an energy principle of structures

Early attempts to use energy derivatives to obtain equations of compatibility of elastic strain and identify so-called least work principles are reviewed with particular reference to the work of Cotterill and Castigliano. The influence of Moseley upon Cotterill is noted. The ultimate success of both Crotti and Engesser in providing essential generalisation to embrace non-linear elasticity is described and a proof of the basis upon which Crotti described what has become known as complementary energy principle, is suggested. The significant differences in the approaches adapted by Cotterill, Castigliano, Crotti and Engesser are emphasised. It appears that Engesser was alone in using the principle of virtual work to derive what he named the principle of minimum complementary energy.