No abstract

The Notch ligand delta-like ligand 4 (Dll4), upregulated by VEGF, is a key regulator of vessel morphogenesis and function, controlling tip and stalk cell selection during sprouting angiogenesis. Inhibition of Dll4 results in hypersprouting, nonfunctional, poorly perfused vessels, suggesting a role for Dll4 in the formation of mature, reactive, functional vessels, with low permeability and able to restrict fluid and solute exchange. We tested the hypothesis that Dll4 controls transvascular fluid exchange. A recombinant protein expressing only the extracellular portion of Dll4 [soluble Dll4 (sDll4)] induced Notch signaling in endothelial cells (ECs), resulting in increased expression of vascular-endothelial cadherin, but not the tight junctional protein zonula occludens 1, at intercellular junctions. sDll4 decreased the permeability of FITC-labeled albumin across EC monolayers, and this effect was abrogated by coculture with the γ-secretase inhibitor N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester. One of the known molecular effectors responsible for strengthening EC-EC contacts is PKA, so we tested the effect of modulation of PKA on the sDll4-mediated reduction of permeability. Inhibition of PKA reversed the sDll4-mediated reduction in permeability and reduced expression of the Notch target gene Hey1. Knockdown of PKA reduced sDLL4-mediated vascular-endothelial cadherin junctional expression. sDll4 also caused a significant decrease in the hydraulic conductivity of rat mesenteric microvessels in vivo. This reduction was abolished upon coperfusion with the PKA inhibitor H89 dihydrochloride. These results indicate that Dll4 signaling through Notch activation acts through a cAMP/PKA pathway upon intercellular adherens junctions, but not tight junctions, to regulate endothelial barrier function. NEW & NOTEWORTHY Notch signaling reduces vascular permeability through stimulation of cAMP-dependent protein kinase A.

No abstract

To the reader it might appear that Dr. Doll was intent on seeing that a straight line should go through the datal points; but if we proceed on the usual lines by joining up points in sequence we get the graph to the right of Fig. 2, from which it will be seen that there is no simple relation between the death rate from lung cancer and the degree of cigarette-smoking. The people of the U.S.A. are the largest per person cigarette-smoking people in the world, yet their lung-cancer death rate is about the same as that of the people of Switzerland and Denmark, who smoke about onehalf of the cigarette quota of Americans. It is to be accepted as a fact that people in England and Wales with lung cancer do on the whole smoke more cigarettes than control people of the same age group, but the fact that as we go from one country to another no relationship exists between cancer death rates and the degree of cigarettesmoking seems to point to something quite significant; surely there must be some other factor or factors at work. This is not a matter of academic interest but one of high practical importance. If cigarette-smoking is responsible for the majority of deaths from lung cancer, how is it that people in the U.S.A., who smoke about 30% more cigarettes than we do, show a death rate from lung cancer (1950) less than half that of ours ? The respective rates are 120 and 280 per million inhabitants.Whether smoking is, or is not, one of the causes of lung cancer in our midst, there will be few people to dissent from the warning given by the Minister of Health (February, 1954) to young people on the dangers of excessive smoking. All excess is bad.SIDNEY RUSS, C.B.E., D.SC. Fatal Case of Toxic Hepatitis Implicating ChlorpromazineChlorpromazine has been used on 500 psychiatric cases (to be reported subsequently), of which six developed jaundice. The one ending fatally is here described. The issue is clouded by the fact that three cases diagnosed as infective hepatitis have occurred concurrently in patients who had never received chlorpromazine or other liver toxin. rhese cases have been clinically and biochemically indistinguishable from the chlorpromazine cases. The incidence of jaundice in the latter, however, is significantly higher than among the rest of the hospital population.CASE REPORT The patient, a woman aged 45, with a recent history, was admitted in a severely disturbed, excited, restless, overactive state with a paranoid psychosis. She showed a mitral stenosis, normally asymptomatic, which at her current level of activity led to dyspnoea and cyanosis. Her blood pressure was 130/80. As sedation was not consistently successful, she was given oral chlorpromazine, the dosage being quickly stepped up to 500 mg. a day. Aided by amylobarbitone sodium in doses not exceeding 36 gr. (2.4 g.) a day, the excitement and overactivity abated, the mental content becoming progressively more rational and coherent. After three weeks of this regime, when 10 g. of chlorpromazine had been consumed, jaundice appeared, so the drug was...